Resveratrol Nanoformulations for Cancer Management: A Comprehensive Review of Disease-Specific Strategies and Clinical Translational Barriers

Abstract

Cancer remains a leading cause of mortality worldwide, highlighting the need for therapeutic strategies that reduce systemic toxicity and drug resistance. Resveratrol (RES), a natural polyphenolic stilbenoid, possesses antioxidant, anti-inflammatory, pro-apoptotic, anti-metastatic, and chemosensitizing activities. However, its clinical translation is limited by poor aqueous solubility, chemical instability, rapid metabolic clearance, and consequently low systemic bioavailability. Nanotechnology-based drug delivery systems provide a promising strategy to address these limitations. This review summarizes recent advances in RES-loaded nanoformulations, including polymeric nanoparticles, liposomes, solid lipid nanoparticles, micelles, inorganic nanocarriers, protein-based systems, and biomimetic vesicles. Their therapeutic performance is evaluated across prostate, lung, colorectal, breast, and other cancers, with attention to tumor targeting, controlled release, combination therapy, multidrug-resistance reversal, and modulation of cancer-relevant pathways such as NF-κB, p53, and PI3K/Akt/mTOR. Current oncology-related clinical evidence for RES is still largely based on conventional oral or micronized formulations. Translation of engineered RES nanocarriers therefore requires stronger evidence on scalable manufacturing, carrier-specific safety, heterogeneous tumor delivery, and biomarker-guided trial design. This review also introduces a semi-quantitative prioritization framework based on model-readiness, translational priority, and safety-alert scoring for future PBPK, PK-PD, nano-QSAR, and machine-learning analyses.

Introduction

According to GLOBOCAN 2022, approximately 20.0 million new cancer cases and 9.7 million cancer deaths occurred worldwide in 2022. Lung cancer remains the leading cause of cancer mortality globally, whereas breast cancer represents the leading cause of cancer death among females; cervical cancer also constitutes a major female cancer burden, particularly in lower-HDI regions.^1,2 Although surgery, chemotherapy, radiotherapy, and targeted therapy remain central to cancer management, their therapeutic benefits are frequently constrained by recurrence, drug resistance, off-target toxicity, and limited tumor selectivity.^3,4 These limitations highlight the need for therapeutic strategies that can improve tumor-specific drug exposure while reducing systemic adverse effects.

To overcome these constraints, plant-derived anticancer agents have gained increasing attention as adjunctive or alternative therapeutic candidates in selected contexts. Resveratrol (RES), a polyphenolic stilbenoid found in grapes, berries, and peanuts, has been extensively investigated because of its antioxidant, anti-inflammatory, pro-apoptotic, anti-metastatic, and chemosensitizing properties.^5,6 Nevertheless, although RES has shown broad anticancer potential across diverse experimental models, the in vivo translation of orally administered free RES remains substantially constrained by poor aqueous solubility, chemical instability, photodegradation, rapid metabolic clearance, and consequently low systemic exposure, making formulation strategies essential for improving its pharmacokinetic performance.^7,8

Nanoparticles (NPs) provide a versatile strategy for improving the delivery of hydrophobic compounds such as RES by enhancing solubility, protecting unstable payloads, prolonging systemic exposure, and enabling tumor-directed delivery. This review therefore examines RES-loaded nanoformulations, including polymeric NPs, liposomes, solid lipid nanoparticles (SLNs), micelles, gold NPs, mesoporous silica nanoparticles, cyclodextrin-based systems, protein-based NPs, and biomimetic exosomes, with emphasis on their design rationale, mechanistic basis, and cancer-specific performance.

Although several reviews of RES nanoformulations have been published in recent years, the present review extends the field in four important respects.^7,9 First, rather than organizing the evidence primarily by carrier category, we adopt a disease-stratified framework to compare nanocarrier performance within prostate, lung, colorectal, breast, and other cancers. This structure facilitates disease-specific comparison of competing platforms and highlights how tumor biology, route of administration, and resistance mechanisms influence carrier selection. Second, we provide an updated analysis of the clinical landscape of RES in oncology, which remains dominated by conventional oral or micronized formulations rather than engineered nanocarriers. In our registry and literature search up to early 2026, the only identified oncology-associated human study involving a commercial liposomal RES formulation evaluated supportive-care rather than antitumor endpoints.¹⁰ Third, this review addresses carrier-specific nanotoxicological considerations by distinguishing nanocarrier-related risks from RES payload-related toxicity, with particular attention to the potential pro-oxidant risk associated with nanocarrier-enhanced intracellular RES exposure. Fourth, we propose a clinical-readiness perspective that prioritizes platforms according to regulatory precedent, biodegradation characteristics, manufacturing feasibility, and translational potential. Although preclinical evidence supports the capacity of nanoencapsulation to improve the therapeutic performance of RES, the limited human validation of advanced RES nanocarriers indicates a persistent bench-to-bedside gap.¹¹ Therefore, this review not only summarizes disease-specific preclinical evidence but also examines the principal barriers to translation, including manufacturing scale-up, nanotoxicology, the heterogeneous contribution of the enhanced permeability and retention (EPR) effect, and clinical trial design. Finally, we organize the extracted formulation, efficacy, and safety data into a semi-quantitative prioritization framework.

Resveratrol: Selection Rationale and Biological Basis

Rationale for the Selection of Resveratrol

Numerous plant-derived antioxidants—curcumin, quercetin, epigallocatechin gallate (EGCG), sulforaphane, and others—have been investigated in oncology nanoformulations, and curcumin in particular has advanced multiple nanoscale formulations into registered cancer trials. The decision to focus this review on resveratrol rather than the broader polyphenol class therefore rests on a defined set of attributes that, taken together, make RES a useful model payload for examining the interaction between formulation design and pharmacological response in oncology nanomedicine.

First, RES shows a dose-dependent shift from antioxidant activity to pro-oxidant cytotoxicity, directly linking carrier release kinetics and intracellular delivery efficiency to pharmacodynamic outcome. This feature makes RES particularly suitable for discussing how nanocarrier design may influence therapeutic window, intracellular exposure, and PK-PD relationships.

Second, RES occupies a chemically and mechanistically distinct niche within the polyphenol class. As a stilbene rather than a flavonoid or curcuminoid, RES is among the most extensively characterized direct activators of SIRT1, a deacetylase whose oncologic relevance spans EMT regulation, p53 modulation, and the SIRT1/FOXO3a apoptotic axis. Together, the available mechanistic and formulation literature supports a rational positioning of RES as a multifunctional adjuvant or chemosensitizing payload, particularly in combination nanocarriers for refractory or drug-resistant tumors. This positioning is based on its context-dependent modulation of apoptosis, inflammatory signaling, drug-efflux pathways, and oxidative-stress balance, while its clinical translation still requires carrier-specific pharmacokinetic, pharmacodynamic, and safety validation.

Third, unlike most dietary polyphenols, RES has already entered oncology-associated human evaluation: a commercial liposomal formulation (Warsaw KB/24/2023) has been tested clinically, albeit only for supportive-care endpoints.¹⁰ This limited clinical entry further justifies focusing on RES as a payload whose formulation-dependent efficacy and safety still require systematic evaluation.

Physicochemical Properties, Metabolism, and Pharmacological Profile

RES, chemically designated as 3,5,4′-trihydroxystilbene, is a naturally occurring polyphenolic phytoalexin belonging to the stilbene family. It is found in the roots of Polygonum cuspidatum, grape skins of Vitis vinifera, berries, peanuts, and other botanical sources. Polygonum cuspidatum, known as “Hu Zhang” in Traditional Chinese Medicine, has historically been used in the management of inflammatory and cardiovascular disorders. In modern pharmacology, interest in RES was further stimulated by the “French Paradox” hypothesis, which proposed an association between moderate red wine consumption and reduced cardiovascular risk despite diets rich in saturated fat.¹²

Structurally, RES contains two phenolic rings linked by a styrene double bond and exists as two geometric isomers, cis-RES and trans-RES. It has the molecular formula C₁₄H₁₂O₃ and a molecular weight of approximately 228.24 Da. The trans-isomer is generally more stable and is regarded as the principal bioactive form, whereas exposure to ultraviolet light, elevated temperature, or alkaline pH may promote isomerization and degradation.¹³ RES is lipophilic, has a melting point of approximately 254 °C, and is poorly soluble in water, although it dissolves in organic solvents such as dimethyl sulfoxide, ethanol, and acetone. Its cis- and trans-configurations are shown in Figure 1, and its characteristic fluorescence properties permit analytical detection.¹⁴

Figure 1.

Chemical structures, photoisomerization, and stability characteristics of trans- and cis-resveratrol. Resveratrol (RES; C₁₄H₁₂O₃) exists as two geometric isomers, trans-resveratrol and cis-resveratrol. Trans-RES is the thermodynamically more stable form and is generally regarded as the principal form investigated for biological activity. Exposure to ultraviolet (UV) light can induce trans-to-cis photoisomerization, while elevated temperature and alkaline pH may further compromise RES stability.

Abbreviations: RES, resveratrol; UV, ultraviolet.

These physicochemical features are compounded by unfavorable pharmacokinetics. Although oral absorption of RES can be substantial, unchanged RES undergoes rapid intestinal and hepatic Phase II metabolism, primarily through glucuronidation and sulfation. Consequently, only very low circulating concentrations of parent RES are detected after oral administration.¹⁵

Despite these delivery limitations, RES remains relevant as an oncology payload because it modulates biological processes associated with cancer progression and treatment response, including oxidative stress, inflammation, apoptosis, invasion, and chemosensitivity.^16–20 Its effects on inflammation-related mediators, including tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), support its evaluation in strategies directed at the tumor-associated inflammatory microenvironment.^21,22 In addition, reported protective effects against treatment-associated injury, including doxorubicin-related toxicity, provide a rationale for investigating RES as an adjunctive component of combination regimens rather than solely as a stand-alone cytotoxic agent.²³

Anticancer Properties of Resveratrol

RES has been extensively investigated as a pleiotropic anticancer agent with dual chemopreventive and therapeutic potential. Its antineoplastic efficacy is substantiated by in vitro, in vivo, and clinical studies, demonstrating inhibition of uncontrolled proliferation, induction of apoptosis, and reduction of tumor burden.^24,25 At the signaling level, RES has been reported to modulate multiple cancer-relevant pathways, including NF-κB-, STAT3-, Wnt/β-catenin-, PI3K/Akt/mTOR-, MAPK-, and SIRT1-associated networks. Because these effects vary by tumor type, cellular context, dose, and exposure duration, these pathways are best discussed as context-dependent mechanistic nodes rather than uniformly inhibited or activated targets. The principal molecular targets and mechanisms are summarized in Table 1.

Table 1.

Summary of Molecular Targets and Anticancer Mechanisms of Resveratrol

Target Category	Specific Molecules	Primary Pharmacological Effects
Transcription factors	NF-κB, AP-1, STAT3, HIF-1α, β-catenin, Nrf2, SIRT1	Context-dependently modulates downstream genes governing proliferation, inflammation, metastasis, angiogenesis, invasion, oxidative stress, and treatment response.
Growth factors and protein kinases	EGFR; PKC, MAPK, PI3K/Akt/mTOR axis	Can attenuate receptor phosphorylation and downstream survival signaling in selected models; direction and magnitude depend on tumor type, dose, and exposure duration.
Cell-cycle regulators	p21, p27, CDK4/6–Cyclin D, Rb, E2F	Upregulates CDK inhibitors, sustains Rb hypophosphorylation, blocks E2F-dependent S-phase transcription, and induces G1/S, G0/G1, or G2/M arrest.
Intrinsic apoptotic pathway	Bax, Bcl-2, cytochrome c, caspase-9/3, PARP; AMPK/SIRT1/FOXO3a axis	Promotes Bax activation and Bcl-2 downregulation, leading to ΔΨm dissipation, cytochrome c release, caspase activation, and PARP cleavage; SIRT1/FOXO3a can link apoptosis to cell-cycle arrest.
Inflammatory cytokines and pathways	IKK, IκBα, TNF-α, IL-6, TRAIL	Blocks NF-κB nuclear translocation in many models, reduces pro-inflammatory signaling, and can enhance TRAIL-associated apoptosis.
EMT & metastasis regulators	Snail, Slug, Twist, E-cadherin, Vimentin, N-cadherin; MMP-2/9	Modulates EMT-marker patterns and MMP-2/9-associated matrix remodeling in selected models. EMT reversal should be described as model-dependent rather than universal.
Drug efflux and MDR reversal	P-gp (MDR1); ABC transporters	Can reduce drug-efflux function and/or MDR1/P-gp-associated signaling, increasing intracellular retention of co-delivered chemotherapeutics in selected resistant models.
Metabolic enzymes	FAS, ACLY, COX-2, GSTs, QR2	Impairs lipogenic and inflammatory metabolic programs and may regulate detoxification enzymes involved in treatment response.
Wnt/β-catenin pathway	GSK-3β, β-catenin, c-Myc, Cyclin D1, survivin	Promotes β-catenin degradation and silences downstream oncogenic transcription, particularly in CRC-related mechanistic contexts.
Immune modulation	PD-L1, STAT3, IL-6/JAK2/STAT3, TAMs, CAFs, dendritic cells, CTLs	Immune-checkpoint effects are context-dependent: RES may increase PD-L1 through Snail/Wnt in some lung cancer cells, whereas nano-RES inhibited PD-L1 in an oral-cancer TAM–CAF model; RES can also affect TAM polarization and CTL/dendritic-cell function.
Pro-oxidant duality (dose-dependent)	ROS; intracellular RES Cmax/AUC	Acts mainly as an antioxidant/chemopreventive agent at moderate exposure, but high nanocarrier-enhanced intracellular exposure may generate cytotoxic ROS and safety-relevant pro-oxidant stress.

A central mechanism through which RES exerts its antiproliferative effect is the induction of cell cycle arrest at multiple checkpoints. RES upregulates cyclin-dependent kinase inhibitors p21 and p27, which sequester CDK4/6–Cyclin D complexes and sustain retinoblastoma protein (Rb) in its hypophosphorylated state, thereby blocking the G1/S transition. Depending on the cellular context, RES can also induce G0/G1 or G2/M arrest, establishing cell cycle blockade as a broadly conserved anticancer mechanism across diverse tumor types.^26,27 Cell cycle arrest is mechanistically coupled to the activation of the intrinsic (mitochondrial) apoptotic pathway, the predominant mode of RES-induced cell death. RES promotes Bax translocation to the outer mitochondrial membrane and antagonizes anti-apoptotic Bcl-2 expression,²⁶ leading to mitochondrial membrane potential (ΔΨm) dissipation, cytochrome c release, and engagement of the caspase-9/caspase-3 executioner cascade,²⁸ culminating in PARP cleavage and irreversible apoptotic commitment. In parallel, RES can elevate intracellular Ca2+ and drive mitochondrial Ca2+ overload, which promotes opening of the mitochondrial permeability transition pore (mPTP) and thereby reinforces ΔΨm collapse, cytochrome c release, and caspase-9/caspase-3 activation.²⁹ Notably, the convergence of these two pathways is mediated through the AMPK/SIRT1/FOXO3a signaling axis, whereby SIRT1 activation simultaneously enhances the transcription of pro-apoptotic BH3-only proteins (Bim, PUMA) and reinforces p27-mediated CDK inhibition,^30,31 establishing a positive feedback loop between cell cycle blockade and mitochondrial-mediated apoptosis.

Beyond direct growth inhibition, RES exerts potent anti-inflammatory effects by targeting the NF-κB signaling cascade.^32,33 Specifically, RES inhibits IκB kinase (IKK) activity, thereby blocking the phosphorylation and degradation of IκBα and preventing nuclear translocation of NF-κB subunits. This results in significant downregulation of TNF-α and other pro-inflammatory cytokines across various neoplastic cell lines. Moreover, RES exhibits a synergistic pro-apoptotic effect when combined with TRAIL, enhancing cancer cell sensitivity to programmed cell death.^34,35 RES has also been associated with reduced migration and invasion in multiple tumor models, but its effects on EMT-associated transcription factors and immune-checkpoint regulation should be interpreted as context-dependent rather than uniformly inhibitory. In several cancer models, RES suppresses invasive behavior by modulating EMT-related markers, restoring epithelial characteristics such as E-cadherin expression, reducing mesenchymal markers including Vimentin and N-cadherin, and attenuating MMP-2/9-associated extracellular-matrix remodeling.^35–38 However, the Snail/PD-L1 axis illustrates the need for tumor-specific interpretation: in lung cancer cells, RES has been reported to induce PD-L1 expression through Snail-driven activation of the Wnt pathway,^39,40 whereas nano-formulated RES inhibited PD-L1 in oral cancer cells by disrupting TAM–CAF-associated IL-6/JAK2/STAT3 signaling.^41,42 Thus, RES-related EMT and immune-checkpoint effects should be presented as model- and microenvironment-dependent, with relevance mainly to selected combination strategies.

A pharmacologically significant property of RES is its capacity to reverse multidrug resistance (MDR) by targeting P-glycoprotein (P-gp),⁴³ the major ATP-dependent efflux transporter responsible for reduced intracellular drug accumulation in resistant tumors. RES can contribute to MDR reversal by functionally inhibiting P-gp-mediated drug efflux and suppressing MDR1/P-gp signaling, thereby increasing intracellular accumulation of co-administered cytotoxics such as doxorubicin and paclitaxel and positioning RES as a potent chemosensitizer in combination regimens.^44,45

Finally, RES modulates a spectrum of enzymes implicated in metabolic reprogramming and carcinogenesis. It reduces hepatic and intratumoral expression of ACLY and FAS, impeding de novo lipogenesis essential for rapid tumor proliferation.^46–50 RES also suppresses COX-2 activity both directly and at the transcriptional level, inhibiting catalytic function and mRNA expression.^51,52 Additionally, RES regulates detoxification enzymes such as glutathione S-transferases (GSTs) and quinone reductase 2 (QR2), which may contribute to overcoming MDR. In colorectal cancer specifically, RES inhibits the Wnt/β-catenin signaling axis by promoting GSK-3β-mediated phosphorylation and proteasomal degradation of cytoplasmic β-catenin, thereby silencing downstream oncogenes including c-Myc, Cyclin D1, and survivin.^53–55

Importantly, RES exhibits a dose-dependent functional shift: moderate exposure may support antioxidant and chemopreventive effects, whereas high intracellular exposure—potentially enhanced by nanocarrier delivery—may induce cytotoxic ROS generation and pro-oxidant activity.^7,56 This property is directly relevant to nanoformulation design.

Collectively, these multitarget mechanisms provide the pharmacological foundation for the cancer-specific nanoformulation strategies discussed below.

Nanocarrier Rationale and Delivery Barriers for Resveratrol

Formulation Rationale for RES Nanocarriers

Translating the anticancer potential of RES into therapeutically meaningful exposure requires formulation strategies that address both its pharmaceutical limitations and the delivery requirements of individual malignancies. Nanoformulation is therefore intended not merely to increase the administered amount of RES, but to improve its physicochemical performance, regulate release and biodistribution, enhance tumor-associated exposure, and support rational combination therapy.

Poor Aqueous Solubility and Chemical Instability

RES has very limited aqueous solubility, reported to be below 0.05 mg/mL at 25 °C, and is commonly classified as a Biopharmaceutics Classification System (BCS) Class II compound characterized by high permeability but low solubility.^8,57 Its active trans-isomer is also susceptible to environmental degradation, making protection of the payload an important formulation objective. Nanocarriers may address these limitations by increasing apparent solubility and reducing premature loss of bioactive RES. Route-adapted delivery is exemplified by inhalable RES–cyclodextrin complex-loaded biodegradable nanoparticles developed for non-small cell lung cancer models.⁵⁸ In addition, cyclodextrin-based nanosponges have directly demonstrated improved RES solubilization and photostability, supporting the ability of nanostructured carriers to protect unstable stilbenoid payloads.⁵⁹

Rapid Metabolism and Limited Effective Exposure

Improved dissolution alone cannot resolve the pharmacokinetic limitations of RES. Despite substantial oral absorption, extensive intestinal and hepatic glucuronidation and sulfation result in very low systemic availability of unchanged RES; the oral bioavailability of parent RES has been reported to be below 1%.^15,60 Accordingly, nanoformulation should be matched to the intended route of administration and therapeutic objective. For systemically administered carriers, prolonged circulation and controlled release may increase the opportunity for tumor-associated exposure, whereas locally or regionally oriented delivery systems may be more appropriate where direct access to the disease site is feasible.^7,61

Absence of Inherent Tumor Selectivity

Free RES has no engineered mechanism for preferential localization in malignant tissue. Nanocarriers can introduce passive or active targeting functions intended to increase tumor-associated delivery while limiting unnecessary exposure of non-malignant tissues. Passive targeting through the enhanced permeability and retention (EPR) effect may contribute to nanoparticle accumulation in solid tumors; however, its clinical reliability is limited and heterogeneous. Quantitative analyses have reported median tumor delivery efficiencies of only approximately 0.7–0.8% of the injected nanoparticle dose, emphasizing that EPR-mediated accumulation should be regarded as contributory rather than sufficient for successful delivery.^62–64

Active targeting strategies use surface-conjugated ligands such as folic acid and hyaluronic acid to enhance uptake in receptor-expressing tumors,^65,66 although their in vivo precision may be reduced by serum-protein adsorption and protein-corona formation.^67–69

Moderate Single-Agent Potency and the Rationale for Combination Delivery

Although RES modulates multiple cancer-relevant pathways, its potency as a single anticancer agent is generally modest relative to conventional cytotoxic or targeted drugs. This feature supports the development of co-delivery systems in which RES functions as a chemosensitizing or multidrug-resistance-modulating payload alongside agents such as doxorubicin or paclitaxel.⁵⁶ In addition, selected carrier components, including poloxamer block copolymers and D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), may further support combination therapy by reducing P-glycoprotein-mediated drug efflux and increasing intracellular retention of co-delivered agents.⁷⁰ Importantly, controlled release remains preferable to indiscriminate maximization of intracellular RES exposure because excessively high local concentrations may increase oxidative injury risk.

Collectively, RES nanoformulation is justified by a combination of pharmaceutical barriers—poor solubility, chemical instability, and rapid metabolic conversion—and oncology-specific requirements, including tumor-associated exposure, controlled release, and combination delivery. Multifunctional nanocarriers provide an opportunity to address several of these limitations within a single delivery system; however, their ultimate value depends on administration route, tumor biology, manufacturing reproducibility, and safety evaluation.

Physical Barriers to RES Delivery

The in vivo translation of RES nanocarriers is constrained not only by the molecular limitations of RES but also by sequential delivery barriers, including systemic clearance, vascular extravasation, stromal penetration, cellular uptake, and intracellular trafficking. Because losses at each stage compound across the delivery process, carrier design must be matched to the dominant barrier in each tumor type rather than relying on a single universal optimization strategy.

Systemic Circulation and Mononuclear Phagocyte Clearance

Following intravenous administration, RES nanocarriers are immediately confronted by the mononuclear phagocyte system (MPS, historically termed the reticuloendothelial system), which rapidly opsonizes circulating particles through adsorption of plasma proteins—including immunoglobulins, complement factors, and apolipoproteins—and sequesters them within the liver and spleen. This dynamic protein corona formation can substantially alter both pharmacokinetics and biodistribution within minutes of injection, often eliminating a major fraction of the administered dose before tumor accumulation can occur.⁷¹ PEGylation remains the most widely adopted countermeasure, conferring stealth properties by sterically hindering protein adsorption and prolonging systemic circulation half-life. Nevertheless, PEG coatings provide only partial mitigation and introduce their own complications, including the so-called “PEG dilemma”, wherein the same hydrophilic corona that prevents opsonization simultaneously impedes tumor cell uptake, as well as the emerging issue of accelerated blood clearance upon repeated dosing.⁷²

Tumor Vascular Extravasation

Nanocarriers that survive systemic circulation must subsequently extravasate from tumor vasculature into the tumor parenchyma. While the classical EPR paradigm posited that fenestrations within neoangiogenic vessels passively permit nanoparticle accumulation for carriers within the 10–100 nm size range, recent mechanistic evidence has fundamentally revised this view. Recent intravital-imaging and modeling studies suggest that endothelial transcytosis may contribute substantially to nanoparticle entry into solid tumors, implying that passive size-based EPR optimization alone may be insufficient and that transendothelial transport pathways could be a more impactful design target for tumor accumulation. The clinical relevance of this barrier is reflected in the low single-digit percentage of injected dose that typically reaches solid tumors.^63,73

Hostile Tumor Microenvironment: Dense ECM, Elevated IFP, and Regional Hypoxia

After extravasation, RES nanocarriers encounter dense ECM, elevated IFP, and regional hypoxia, which jointly restrict penetration and may reinforce drug resistance.^64,65 Leaky vasculature, vessel compression, and dysfunctional lymphatic drainage further raise interstitial fluid pressure (IFP) until the convective driving force collapses, confining extravasated carriers to a narrow perivascular zone.⁶⁴ Aberrant angiogenesis adds chronic hypoxia, which restricts delivery to tumor cores and drives HIF-1α–mediated upregulation of efflux transporters (eg, P-glycoprotein), coupling the physical barrier to biochemical resistance.⁶⁵ Critically, these three features are self-reinforcing—stromal stiffening compresses vessels and worsens hypoxia, hypoxia stimulates further matrix deposition, and elevated IFP impedes penetration into the resulting hypoxic niches. Engineering responses have therefore moved beyond size minimization toward enzymatic stromal modulation (collagenase, hyaluronidase, relaxin)⁷⁴ and stimuli-responsive carriers, while ultrasmall (<50 nm), near-neutral particles retain a penetration advantage.⁷³

Cellular Internalization and Intracellular Trafficking

Even upon reaching the tumor cell surface, nanocarriers must overcome the plasma membrane barrier through endocytic uptake—most commonly via clathrin-mediated, caveolae-mediated, or macropinocytic pathways. Although the efficiency of internalization is governed by particle size, surface chemistry, and the density and identity of conjugated targeting ligands, the in vivo formation of a protein corona can sterically mask these ligands and divert intracellular trafficking, attenuating the targeting precision achieved in vitro.⁷¹ Once internalized, nanocarriers are typically routed into endolysosomal compartments, where the acidic and hydrolytic environment risks degrading both the carrier and the bioactive RES payload before therapeutic release into the cytosol. Engineered strategies—such as pH-responsive bonds, fusogenic lipids, and proton-sponge polymers—are therefore essential to ensure timely endosomal escape and bioactive RES release at the intended subcellular site of action.^65,66

Overview of Nanocarrier Platforms for Resveratrol Delivery

Table 2 summarizes the principal nanocarrier platforms evaluated for RES encapsulation, including their defining structural features, key physicochemical advantages and limitations, and primary therapeutic niches, so that the cancer-specific analyses below can focus on how each platform addresses the challenges of individual malignancies.

Table 2.

Consolidated Overview of Principal Nanocarrier Platforms for RES Delivery

Nanocarrier Platform	Key Advantages	Key Limitations	Primary Therapeutic Niche	Typical Size
Polymeric NPs	Biodegradable; tunable release; compatible with ligand, pH, redox, and gene–drug co-delivery designs	Passive EPR dependence unless functionalized; burst release and scale-up variability	Baseline and smart functionalization platform across prostate, lung, CRC, and breast cancer	100–250 nm
Liposomes	Biomimetic bilayer; strong co-delivery precedent; useful for MDR reversal and cardioprotection strategies	Storage instability; opsonization/CARPA risk; bile-salt destabilization for oral CRC use	IV combination therapy; resistant breast/lung cancer; stromal or immune-pathway modulation	70–150 nm
SLNs/NLCs/liquid-crystalline lipid NPs	High physical stability; high EE; oral, pulmonary, topical, and microneedle-compatible delivery	Lipid polymorphism; matrix expulsion; active lipid excipients may confound RES-specific effects	Pulmonary deposition, CRC oral release, topical/locoregional delivery, lipid co-delivery	90–200 nm
Lipid–polymer hybrid nanocarriers	Combine lipid surface stability with polymeric core control; allow ligand and stimuli-responsive release	More complex CMC, reproducibility, and scale-up; carrier-by-carrier safety validation required	Targeted NSCLC delivery; systemic combination therapy; microenvironment-responsive release	80–250 nm
Polymeric micelles/polyprodrug NPs	Small size and tumor penetration; solubilization; redox- or pH-responsive self-assembly; possible P-gp modulation	Low loading or premature disassembly below CMC; off-target transporter effects	MDR-oriented lung/breast delivery; systemic co-delivery; metastasis-oriented models	40–100 nm
Cyclodextrin complexes /nanosponges	Strong solubilization and photostability improvement; host–guest simplicity; oral feasibility	Limited active targeting; nanosponge scalability; β-CD renal/cholesterol-extraction concerns at high systemic exposure	Solubility-limited applications; cervical inclusion complex; prostate/CRC nanosponges	100–500 nm
Protein-based NPs (albumin, zein, casein, sericin)	Biodegradable; albumin precedent; food-grade oral matrices; possible gp60/SPARC relevance	Batch variability; immunogenicity/endotoxin control; uptake mechanisms often unvalidated	Breast/ovarian albumin systems; oral CRC and breast protein carriers; sericin pH-responsive systems	80–200 nm
Polysaccharide/chitosan systems	Mucoadhesion; cationic surface interaction; oral/local delivery; simple ionic crosslinking	Nonspecific protein adsorption; MPS uptake; variable deacetylation/MW; cationic toxicity at high density	CRC oral delivery; oral/cervical/local mucosal delivery; radiosensitizing chitosan systems	100–250 nm
Inorganic/metallic NPs (Au, Pd, Ag)	Theranostic, photothermal, radionuclide, and green-synthesis functions; high imaging/photothermal utility	Non-biodegradability; metal retention; carrier-derived cytotoxic/ROS effects; long-term disposition uncertain	Local theranostics, PTT combinations, metal-assisted proof-of-concept delivery	20–60 nm core
Mesoporous silica/MOF/ZIF-8	High surface area and loading; pore-gated or pH-responsive release; nucleic-acid/drug co-delivery possible	Non-biodegradable or incompletely degradable; hemolysis/cytokine risks; unclear long-term fate	Gastric RES/anti-miR21 delivery; prostate/breast/CRC intracellular release; ZIF-8 CRC pH response	50–200 nm
Biomimetic and cell-derived carriers	Biological membrane interfaces; tissue delivery; exosomal RES transport; potential immune evasion	Heterogeneous cargo; quality control and scale-up unresolved; uptake/MDR claims require direct validation	Milk-exosome breast delivery; CRC biomimetic ferroptosis platforms	80–150 nm
Magnetic/niosomal platforms	Magnetic responsiveness; vesicular encapsulation; possible external guidance or hyperthermia	Iron-related ROS, field penetration limits, and early evidence base	Pancreatic cell-based magnetic niosomal RES delivery; experimental locoregional strategies	<100 nm core; vesicles variable

Beyond conventional nanocarrier categories, RES delivery has begun to intersect with nucleic-acid nanomedicine. Early studies combining RES with BCR-ABL siRNA in leukemia models⁷⁵ and anti-miR21 in gastric carcinoma,^76,77 support proof of concept for gene–drug co-delivery, in which phytochemical modulation is paired with pathway-level intervention.

Prostate Cancer

Prostate-cancer-directed RES nanocarriers include lipid-based, polymeric, inorganic/metallic, and natural-macromolecule platforms. The available evidence remains predominantly preclinical and varies according to model type, administration route, and whether RES is used as a single payload or as a chemosensitizing co-payload. Figure 2 summarizes representative delivery-to-action mechanisms, including receptor-associated uptake, controlled intracellular RES release, cell-cycle arrest, and apoptosis.

Figure 2.

Integrated resveratrol nanocarrier-mediated delivery and therapeutic mechanisms in prostate cancer. This schematic summarizes representative mechanisms reported for different resveratrol (RES) nanocarrier platforms in prostate cancer and does not depict a single formulation possessing all of the functions shown. Folate-functionalized RES-loaded PLGA–chitosan nanoparticles are illustrated as binding to folate receptor alpha (FRα) on FRα-overexpressing prostate cancer (PCa) cells, followed by receptor-associated cellular uptake and controlled intracellular RES release. Released RES is depicted as engaging two interconnected therapeutic programs. In the cell-cycle module, increased p21 and p27 restrain CDK4/6–Cyclin D activity, thereby limiting Rb/E2F-dependent G1/S progression and inducing cell-cycle arrest. In the mitochondrial apoptosis module, mitochondrial dysfunction promotes cytochrome c release, apoptosome formation, procaspase-9 activation, subsequent caspase-3/-7 activation, and apoptosis. The lower-right crosstalk module illustrates AMPK/SIRT1/FOXO3a-associated reinforcement of p27-mediated cell-cycle control and Ca²⁺ overload/mPTP-associated mitochondrial apoptosis. Solid or dashed arrows indicate targeting, uptake, intracellular trafficking, release, or downstream signaling progression; upward arrows (↑) indicate increased expression, activation, release, or accumulation; inhibitory T-ended lines indicate suppression of the indicated molecular interaction or pathway; the blocked positions in the cell-cycle diagram indicate interruption of cell-cycle progression.

Abbreviations: FRα, folate receptor alpha; mPTP, mitochondrial permeability transition pore; RES, resveratrol.

Lipid-Based Nanocarriers

Lipid-based RES nanocarriers provide a complementary trajectory to the polymeric and stimuli-responsive systems, particularly in contexts where chemoprevention, systemic exposure, and taxane-based combination therapy are therapeutically relevant. Early in vivo evidence showed that liposomal co-encapsulation of curcumin and RES reduced prostate cancer incidence in prostate-specific PTEN-knockout mice, supporting the concept that liposomal delivery can convert poorly bioavailable phytochemicals into biologically active chemopreventive combinations in genetically driven prostate tumorigenesis.⁷⁸ In parallel, RES-loaded solid lipid nanoparticles (RSV-SLNs) have extended this strategy from chemoprevention to pharmacokinetic optimization: their prolonged circulation and enhanced prostate biodistribution indicate that lipid matrices can improve both systemic persistence and tissue-level exposure of RES.⁷⁹ More recently, PEGylated liposomes co-delivering docetaxel and RES provided a prostate-specific chemotherapy-sensitizing platform, integrating the cytotoxic potency of docetaxel with the MDR-modulating and pro-apoptotic properties of RES within a single nanoscale carrier.⁸⁰

Overall, lipid-based prostate-cancer studies support three main uses: chemopreventive phytochemical co-delivery, improved RES exposure, and docetaxel-associated chemosensitization. At present, their treatment-oriented value is strongest as exposure-optimizing or combination-delivery platforms rather than as RES monotherapy systems.

Polymeric Nanocarriers

RES-loaded polymeric nanoparticles based on a poly(ε-caprolactone) (PCL) and poly(D,L-lactic-co-glycolic acid)-poly(ethylene glycol) (PLGA-PEG) blend were prepared by nanoprecipitation to evaluate RES delivery in prostate cancer models. In the Sanna et al⁸¹ study, nanoencapsulation improved cytotoxicity against DU-145, PC-3, and LNCaP cells compared with free RES, and confocal microscopy confirmed cellular uptake of fluorescently labeled nanoparticles. These findings support in vitro prostate-cancer activity, whereas in vivo efficacy remains to be validated. A separate PLGA-based RES formulation further supported apoptosis-related programmed cell death and G1/S cell-cycle arrest in prostate cancer cells.⁸² Mechanistically, this arrest reflects the p21/p27-mediated inhibition of CDK4/6–Cyclin D and the consequent Rb hypophosphorylation that blocks the G1/S transition in prostate cancer cells. Beyond direct G1/S blockade, the cell-cycle and apoptotic programs engaged by RES in prostate cancer are mechanistically interconnected. In LNCaP cells, RES inhibits PI3K/Akt signaling to drive FOXO nuclear translocation and transcription of p27^KIP1 and pro-apoptotic effectors,⁸³ while in PC3 and 22RV1 cells RES activates an ATM–AMPK–p53–p21/p27 axis that reinforces G1/S arrest.⁸⁴ In parallel, RES triggers Bax oligomerization, mitochondrial membrane-potential dissipation, and cytochrome-c–dependent caspase-9/-3 activation in prostate cancer cells,⁸⁵ and resveratrol-loaded nanoparticles reproduce this dual response—G1/S arrest together with dose-dependent loss of mitochondrial membrane potential and elevated caspase-3 activity—in LNCaP cells.⁸⁶ This convergence of AMPK/SIRT1/FOXO3a-linked cell-cycle control and mitochondrial (Ca²⁺-associated) apoptosis provides the prostate-cancer–specific basis for the crosstalk module. For future translation, reproducible preparation will be important because bulk nanoprecipitation may broaden size distribution and release variability; continuous-flow microfluidic synthesis may help improve batch consistency.⁸⁷ Continuous-flow microfluidic synthesis offers a direct engineering response, providing microsecond-scale mixing within picoliter channel volumes to yield PLGA nanoparticles with PDI typically below 0.1 and scale-independent reproducibility from milligram to gram-scale production—a strategy worth evaluating for prostate-targeted RES-PLGA development.⁸⁸

Beyond conventional polymeric carriers, ligand-functionalized polymeric NPs have been explicitly developed to enhance the precision of RES delivery to prostate malignancies through receptor-mediated targeting. Folate receptor alpha (FRα) is a clinically relevant and differentially expressed target in prostate cancer models; tissue microarray analysis of patient-derived prostate carcinoma specimens has demonstrated significantly elevated FRα expression in malignant tissue compared to adjacent normal tissue, with notably higher expression in poorly differentiated and docetaxel-resistant lesions.⁸⁹

In a representative folate-targeted study, Singh et al⁸⁹ fabricated planetary ball-milled (PBM) nanoparticles encapsulating RES alone or co-loaded with docetaxel (DTX), with surface conjugation of folic acid to direct active targeting to FRα-overexpressing prostate cancer cells. Internalization of these FA-conjugated nanoparticles in docetaxel-resistant PC3-R cells was directly demonstrated by transmission electron microscopy showing intracellular nanoparticles, while immunofluorescence co-staining with anti-FRα antibody confirmed nanoparticle colocalization with the folate receptor. In PC3-R cells, the FA-RES nanoformulation reduced the effective RES concentration required for cytotoxicity to approximately 3 μM, while the FA-RES+DTX combination further amplified pro-apoptotic activity, increasing the apoptotic cell fraction to 65.9% versus 8.9% for empty-nanoparticle controls. Mechanistically, FA-RES+DTX nanoparticles downregulated NF-κB p65, COX-2, and the anti-apoptotic markers BCL-2, BCL-XL, and survivin, while inducing the pro-apoptotic markers BAX and BAK and activating caspase-3 cleavage.⁸⁹ A complementary folate-targeted PLGA-chitosan platform (Res-PCF-NPs) developed by Amiri et al⁹⁰ likewise reduced the IC₅₀ in PC-3 cells to approximately 51 μg/mL at 48 h while sparing non-malignant cells, with apoptosis-related gene modulation and ROS generation supporting oxidative-stress–mediated cell death. Surface modification is not limited to folate-mediated targeting. Eroglu⁹¹ developed a resveratrol-loaded poly(2-hydroxyethyl methacrylate)-chitosan nanotherapeutic and evaluated its in vitro activity against PC-3 prostate cancer cells. In this architecture, RES was incorporated into a pHEMA-based nanosystem with chitosan serving as a cationic surface-modifying polymer, thereby introducing a material design distinct from the polyester-based carriers discussed above. The formulation demonstrated effective RES delivery and cytotoxic activity against PC-3 cells, broadening the polymeric evidence base from PLGA/PCL systems to pHEMA–chitosan nanosystems. Nevertheless, because this study was confined to in vitro evaluation, it should be interpreted as proof of material-platform feasibility rather than evidence of tumor-selective delivery or superior in vivo antitumor efficacy.

Inorganic and Metallic Nanocarriers

Inorganic nanocarriers investigated for resveratrol (RES) delivery in prostate cancer now include noble-metal nanoplatforms based on gold or palladium, together with functionalized mesoporous silica nanoparticles (MSNs). Gold-based systems provide evidence ranging from surface-associated RES delivery to local radionuclide-assisted theranostics; resveratrol-functionalized palladium nanoparticles add receptor-associated cellular uptake, immunomodulatory mechanistic evidence, and systemic xenograft efficacy; and MSNs provide controlled RES release with evaluation of docetaxel sensitization under hypoxia-associated resistance.

Among metallic nanoplatforms, resveratrol-conjugated gold nanoparticles (Res-AuNPs) were produced through a green synthesis strategy in which RES participated in gold-ion reduction and remained associated with the nanoparticle surface. In PC-3 prostate cancer cells, increasing the RES corona on AuNPs was associated with improved cellular uptake after 24 h and greater anticancer activity compared with formulations containing a lower RES corona.⁹²

The potential of gold-based RES nanoplatforms was subsequently extended from in vitro delivery to in vivo prostate-tumor treatment through resveratrol-functionalized radioactive gold nanoparticles (RESV–¹⁹⁸AuNPs). In PC-3 tumor-bearing SCID mice, intratumoral administration of RESV–¹⁹⁸AuNPs resulted in retention of more than 85% of the injected dose within the tumor for up to 24 h, and the treated group showed a greater than tenfold reduction in tumor volume relative to saline-treated controls by the fourth week after treatment.⁹³

However, because RESV–¹⁹⁸AuNPs contain a therapeutic radionuclide and were administered intratumorally, the observed tumor suppression supports the local theranostic potential of a RES-functionalized radioactive gold platform rather than demonstrating that non-radioactive or systemically administered Res-AuNPs alone improve RES delivery in prostate cancer.

More recently, non-radioactive resveratrol-functionalized palladium nanoparticles (Res-PdNPs) have partially addressed this evidentiary gap by providing systemic in vivo data. Thipe et al⁹⁴ selected an optimized Res-PdNP formulation, Res-PdNP-4, with a TEM core size of 24 ± 3 nm and a zeta potential of −40 ± 3 mV. In PC-3 cells, laminin-receptor blocking markedly reduced nanoparticle internalization, supporting receptor-associated cellular uptake mediated by the resveratrol corona. Res-PdNPs also exhibited selective in vitro activity, with IC₅₀ values of 7 and 5 μg/mL in PC-3 cells at 48 and 72 h, respectively, whereas no apparent IC₅₀ was observed in normal human aortic endothelial cells. Importantly, intravenous treatment of PC-3 xenograft-bearing SCID mice with 1.0 mg/kg Res-PdNPs reduced tumor volume to 0.06 ± 0.02 cm³ at day 35, compared with 0.37 ± 0.05 cm³ in saline-treated controls. Separate mechanistic experiments further linked this platform to NF-κB modulation, macrophage-polarization-associated responses, and reduced tumor microvessel density. Nevertheless, because the in vivo model was immunodeficient and palladium itself may contribute to therapeutic activity, future studies should distinguish carrier-derived effects from RES-mediated pharmacology and validate long-term metal disposition and immune-related efficacy in more clinically representative models.

Functionalized MSNs provide a distinct and directly RES-focused delivery strategy. Chaudhary et al⁹⁵ encapsulated RES in uniformly sized MSNs of approximately 60 nm and compared phosphonate-functionalized MSNs (PO₃-MSNs) with amine-functionalized MSNs (NH₂-MSNs) in PC3 prostate cancer cells. At pH 7.4, free RES and NH₂-MSN-loaded RES exhibited rapid release approaching 90% within the first 12 h, whereas PO₃-MSN-loaded RES limited release to approximately 50% over the same period. Correspondingly, PO₃-MSN-RES enhanced antiproliferative activity, reducing the IC₅₀ from 14.86 μM for free RES to 7.15 μM, while NH₂-MSN-RES showed weaker activity with an IC₅₀ of 20.45 μM.

The same study further examined whether controlled RES delivery could preserve its chemosensitizing activity under hypoxia-associated docetaxel resistance. In hypoxic PC3 cells, PO₃-MSN-RES produced robust, dose-dependent sensitization to docetaxel, with an effect comparable to that of free RES solution. Thus, the principal contribution of the PO₃-MSN formulation is not evidence of superiority over free RES in docetaxel sensitization, but rather the integration of controlled release, enhanced antiproliferative activity, and retention of RES-mediated chemosensitizing function within a single nanocarrier platform.⁹⁵

Collectively, inorganic RES nanocarriers now delineate three complementary development pathways in prostate cancer. Res-AuNPs demonstrate that a RES-associated surface corona can enhance anticancer activity in PC-3 cells, whereas RESV–¹⁹⁸AuNPs support local radionuclide-assisted tumor retention and treatment. In contrast, systemically administered Res-PdNPs provide non-radioactive in vivo evidence integrating receptor-associated uptake, NF-κB-related mechanistic activity, reduced tumor angiogenesis, and substantial xenograft growth inhibition. PO₃-MSN-RES represents a controlled-release approach that improves RES antiproliferative activity and preserves its ability to sensitize hypoxic PC3 cells to docetaxel. Nevertheless, all of these platforms remain preclinical and still require immune-competent validation, reproducible manufacturing, and clinically relevant dosing strategies.

Protein- and Polysaccharide-Based Nanocarriers

In prostate cancer, cyclodextrin nanosponges, polysaccharide-coated nanoparticles, and alginate-based combination systems mainly support RES solubilization, stability, and formulation feasibility, with in vivo antitumor validation still limited.

To overcome the poor aqueous solubility and photoinstability of RES, β-cyclodextrin (β-CD) has been crosslinked (eg, with carbonyldiimidazole) into nanosponges—porous, hyper-crosslinked three-dimensional polymers that act as genuine nanoscale carriers. The feasibility of this strategy for RES was first established by Ansari et al⁹⁶ who complexed RES within carbonyldiimidazole-crosslinked β-CD nanosponges (400–500 nm) and demonstrated markedly enhanced aqueous solubility, improved photostability, and increased in vitro permeation relative to free RES, while the blank carrier remained non-cytotoxic. Building on this platform, RES and its analogue oxyresveratrol (OXY) were encapsulated within β-CD nanosponges (1:4 drug-to-polymer ratio). Transmission electron microscopy revealed uniform spherical particles, consistent with a dynamic light scattering size of 200–250 nm.⁵⁹ Complexation markedly improved both stability and dissolution. Under UV irradiation, free RES and OXY degraded by 59.7% and 27.5% within 15 min, whereas the loaded nanosponges conferred roughly 2-fold (RES-NS) and 3-fold (OXY-NS) greater photoprotection. The enhanced solubilization also translated into stronger antioxidant (DPPH-scavenging) activity relative to the free compounds.⁵⁹

For prostate cancer, cytotoxicity was assessed by MTT assay against DU-145 cells over 96 h. Both RES- and OXY-loaded nanosponges produced concentration-dependent inhibition of cell viability that was significantly greater than the free drugs—for RES-NS at 25, 50, and 100 µM—while blank nanosponges showed no significant toxicity. The authors attributed this enhancement to the small particle size of the nanocarrier and the higher solubilization of RES and OXY. Consistent with the behavior of this carrier class, an additional study using the RES analogue oxyresveratrol (OXY) complexed with insoluble cyclodextrin nanosponges demonstrated stronger inhibition of PC-3 cell viability than free OXY.⁹⁷ This finding supports the cyclodextrin nanosponge platform, though it does not directly demonstrate RES delivery. Together, the direct RES data in DU-145 cells indicate that cyclodextrin nanosponges can improve RES photostability and antiproliferative activity, while the OXY findings provide complementary platform-level evidence in androgen-independent prostate cancer models. However, the prostate-cancer evidence for RES-loaded cyclodextrin nanosponges remains confined to in vitro evaluation, and additional studies are required to determine whether improved physicochemical stability translates into enhanced tumor exposure or in vivo therapeutic efficacy.

Alginate-based combination nanoparticles provide additional but comparatively early evidence for RES-containing prostate-cancer delivery. Related formulation-level evidence was provided by Sanna et al⁹⁸ who developed RES-loaded PLGA nanoparticles coated with chitosan or alginate and demonstrated improved encapsulation, controlled release, and protection against light-induced RES degradation. Saralkar and Dash⁹⁹ evaluated alginate nanoparticles co-loading curcumin and RES in DU145 cells. Because this was an in vitro co-delivery formulation, it is most appropriately used to support the feasibility of polysaccharide-based RES combination nanocarriers rather than as evidence for RES monotherapy.

Comparative Assessment of Nanocarrier Platforms for Prostate Cancer

A horizontal comparison across prostate-cancer-specific RES nanocarriers reveals distinct strategic niches determined by carrier architecture, disease model, and evidentiary maturity. Lipid-based systems provide the broadest translational range, spanning chemoprevention in genetically driven prostate tumorigenesis, improved systemic persistence and prostate biodistribution, and docetaxel-associated co-delivery. Polymeric systems provide the most direct evidence for intracellular RES delivery and receptor-associated targeting: PCL/PLGA-PEG nanoparticles improved antiproliferative activity and cellular uptake in DU-145, PC-3, and LNCaP cells, whereas folate-functionalized polymeric nanoparticles extended this strategy to FRα-associated uptake and docetaxel-resistant PC3-R models. Chitosan- or pHEMA-associated systems further broaden the polymeric evidence base, although most remain confined to in vitro evaluation.

Inorganic and metallic platforms occupy a different niche. Res-AuNPs and RESV–¹⁹⁸AuNPs support surface-associated delivery and local theranostic treatment, respectively, whereas systemically administered Res-PdNPs provide non-radioactive in vivo evidence involving receptor-associated uptake, NF-κB-related modulation, reduced angiogenesis, and xenograft growth inhibition. PO₃-MSN-RES adds a controlled-release strategy that improves RES antiproliferative activity and preserves docetaxel-sensitizing function under hypoxia-associated resistance. By contrast, cyclodextrin nanosponges and alginate-based systems mainly address RES solubility, photostability, and formulation feasibility, with limited in vivo prostate-cancer validation.

Overall, the most developed prostate-cancer evidence currently comes from functionalized polymeric nanoparticles and systemically evaluated metallic platforms, while lipid-based systems remain particularly relevant for exposure optimization and chemotherapy sensitization. However, uptake mechanisms remain incompletely characterized for several non-targeted RES nanocarriers whose enhanced activity has been inferred mainly from cytotoxicity assays. Future studies should combine endocytosis-inhibitor profiling, endolysosomal colocalization, LC-MS/MS quantification of intracellular free RES, and in vivo biodistribution analysis to distinguish true payload accumulation from altered extracellular release kinetics or carrier-associated fluorescence signals. For prostate-targeted carriers, release kinetics should be optimized to maintain intracellular RES within a therapeutic window rather than simply maximize uptake, because excessive endocytic delivery may shift RES toward pro-oxidant activity in adjacent normal prostatic tissue.

Lung Cancer

Lung cancer continues to be the primary cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) constituting the majority of diagnosed cases.¹⁰⁰ RES has been reported to suppress lung cancer cell proliferation and promote apoptosis through multiple context-dependent mechanisms, including mitochondrial dysfunction, oxidative-stress regulation, inflammatory signaling, and kinase-associated survival pathways; however, its therapeutic translation remains limited by poor physicochemical stability and insufficient effective pulmonary exposure. Lung cancer poses unique drug delivery challenges, including the option of direct pulmonary administration via inhalation, the need for deep parenchymal penetration, and the high prevalence of MDR in advanced NSCLC.

Among these platforms, lipid-based carriers, lipid–polymer hybrid nanoparticles, polymeric micelles, inhalable cyclodextrin–polymeric nanoparticles, stimuli-responsive polymeric nanoparticles, and inorganic nanocarriers have been investigated for RES delivery in lung cancer, as illustrated in Figure 3. These systems address distinct therapeutic objectives, including pulmonary deposition, receptor-mediated tumor-cell uptake, intracellular stimulus-responsive release, enhancement of mitochondrial apoptosis, reversal of drug resistance, and modulation of inflammation- or immune-metabolism-associated therapeutic responses.

Figure 3.

Complementary resveratrol nanocarrier strategies in lung cancer: CD93-directed immune-metabolic reprogramming and EGFR-targeted ROS-responsive combination delivery. This schematic integrates two distinct RES nanocarrier-based therapeutic concepts in lung cancer rather than representing a single multifunctional nanoplatform. In the left panel, CD93-targeted RES-loaded nanoparticles are illustrated as interacting with CD93-associated CD8⁺ tumor-infiltrating T cells and modulating an AKT/PAK5/AIF-associated metabolic program. The depicted functional consequences include increased oxygen consumption rate (OCR), interferon-γ (IFN-γ), and granzyme B (GZMB), together with decreased expression of the exhaustion-associated markers PD-1, Tim-3, and Lag-3. In the right panel, an EGFR-targeted, ROS-responsive nanocarrier co-delivering RES and docetaxel (DTX) is illustrated as undergoing receptor-mediated endocytosis and intracellular ROS-associated payload release, thereby reducing drug efflux and increasing intracellular drug accumulation. The downstream mitochondrial apoptotic response is represented by increased Bax, decreased Bcl-2, cytochrome c release, caspase activation, and apoptosis, together with decreased matrix metalloproteinases (MMPs) associated with reduced invasive potential. Solid or curved arrows indicate targeting, endocytosis, intracellular release, transport, or downstream signaling progression; upward arrows (↑) indicate increased levels or activity; downward arrows (↓) indicate reduced levels or activity; inhibitory or crossed blockade symbols indicate suppression of drug efflux or the indicated molecular process; red jagged symbols labeled ROS indicate increased reactive oxygen species.

Abbreviations: AIF, apoptosis-inducing factor; DTX, docetaxel; EGFR, epidermal growth factor receptor; GZMB, granzyme B; MMPs, matrix metalloproteinases; OCR, oxygen consumption rate; RES, resveratrol.

Lipid-Based Nanocarriers

Liposomal delivery systems have been extensively investigated to overcome RES hydrophobicity and improve its deposition in lung tissues. A more directly supported liposomal strategy in lung cancer is mitochondrial-targeted RES liposomes. Wang et al¹⁰¹ developed dequalinium-modified PEG-DSPE RES liposomes engineered to concentrate RES near mitochondria rather than act as passive solubilizers. By dissipating mitochondrial membrane potential and activating mitochondria-associated apoptotic pathways, these liposomes induced apoptosis in both non-resistant and resistant lung cancer cells, supporting liposomal RES delivery as a strategy for overcoming apoptosis resistance.

A newer liposomal lung-cancer study further extends this platform from mitochondrial targeting to inflammatory pathway modulation: Chen et al¹⁰² reported that RES liposomes alleviated lung cancer progression in vivo by targeting the TLR4/NLRP3 inflammasome pathway and enhancing anti-tumor immune responses. This study provides in vivo support for liposomal RES beyond resistant-cell apoptosis models.

However, passive EPR-dependent delivery alone is unlikely to fully address the anatomical and biological complexity of pulmonary malignancies. For lung cancer, lipid-based RES delivery therefore needs to be considered according to both route adaptation and antitumor evidence. Structurally stable lipid matrices, including solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs), are particularly relevant because they can improve RES stability, support controlled release, and may be adapted for localized pulmonary administration.

Pulmonary-deposition-oriented NLCs provide formulation-level evidence for route-adapted RES delivery. Khan et al¹⁰³ developed trans-resveratrol-loaded nanostructured lipid carriers (TRES-NLCs) with particle sizes below 145 nm, narrow size distributions, high encapsulation efficiencies exceeding 96%, and aerosol-deposition characteristics compatible with pulmonary delivery. A subsequent study further evaluated trans-resveratrol-loaded NLCs delivered through medical nebulizers and reported physicochemical and aerosolization properties supporting deposition in the middle-to-peripheral lung regions.¹⁰⁴ Together, these studies support the feasibility of non-invasive pulmonary RES delivery, but they should be interpreted as formulation and deposition evidence rather than direct proof of antitumor efficacy in lung-cancer-bearing animals.

By contrast, several RES-containing lipid nanocarriers have provided more direct therapeutic evidence in lung cancer models. Abdelaziz et al¹⁰⁵ developed ion-paired liquid crystalline nanoparticles co-delivering pemetrexed (PMX) and RES (PMX-RSV-LCNPs). In A549 cells, the optimized formulation enhanced cellular uptake and cytotoxicity relative to the free-drug combination. In urethane-induced lung cancer-bearing mice, PMX-RSV-LCNPs reduced tumor-associated lung burden, decreased VEGF expression, increased caspase-3, and improved histopathological and safety profiles compared with free PMX/RES. This study provides a treatment-oriented lipid nanocarrier example linking RES co-delivery with anti-angiogenic, pro-apoptotic, and safety-related outcomes. A complementary strategy was reported by Asadollahi et al¹⁰⁶ who co-loaded erlotinib (ELT) and RES into NLCs for NSCLC therapy. The optimized ELT/RES-NLCs had a particle size of approximately 97.5 nm and high encapsulation efficiencies for both drugs. In A549 cells, this co-delivery system reduced cell viability, increased apoptosis, induced G2/M cell-cycle arrest, upregulated BAX, p53, and cleaved caspase-3/-9, and downregulated survivin and Bcl-2. This formulation extends lipid-based RES delivery from cytotoxic-drug combinations to integration with an EGFR-directed small-molecule therapy.

Lipid–polymer hybrid nanoparticles further advance this evidence by combining lipid-associated stability with polymeric structural control and ligand- or stimulus-responsive release. Song et al¹⁰⁷ developed epidermal growth factor (EGF)-conjugated, reactive oxygen species (ROS)-responsive lipid–polymer hybrid nanoparticles co-encapsulating docetaxel (DTX) and RES for NSCLC therapy. This platform was designed to integrate EGF/EGFR-associated tumor-cell delivery with ROS-responsive intracellular co-release of DTX and RES in the oxidative tumor-cell environment. In vitro and in vivo evaluation demonstrated synergistic therapeutic activity, stronger tumor inhibition, and reduced systemic toxicity relative to comparator treatments. A second hybrid strategy was reported by Das et al¹⁰⁸ who developed folate-integrated, pH-responsive lipid–polymer hybrid nanocarriers loaded with RES (FOL-RSV-LPHNCs). The optimized formulation showed a particle size of approximately 248 nm, an encapsulation efficiency of approximately 94%, and substantially greater RES release at acidic pH than at physiological pH. In A549 cells, it showed selective internalization and enhanced anticancer activity with limited toxicity toward Wi-38 cells; in an A549 xenograft model, intravenous FOL-RSV-LPHNCs prolonged systemic exposure relative to free RES and markedly suppressed tumor growth. Together, these hybrid systems provide stronger disease-specific evidence than pulmonary-deposition-oriented NLCs because they combine tumor targeting, microenvironment-responsive release, pharmacokinetic improvement, and in vivo antitumor activity.

Simple RES-SLN monotherapy should be presented more cautiously. SLNs and NLCs are useful lipid matrices for hydrophobic phytochemicals because they improve physical stability and support sustained release. RES-loaded SLNs formulated with stearic acid/lecithin matrices have shown particle sizes in the 100–200 nm range, negative zeta potentials, encapsulation efficiencies exceeding 85%, enhanced photostability, sustained release, and improved oral bioavailability in formulation studies.¹⁰⁹ However, quantitative tumor-volume reduction data and full pharmacokinetic profiles for systemically administered RES-SLNs in A549 lung-cancer xenografts remain insufficiently established in the peer-reviewed literature. Therefore, in lung cancer, lipid-based evidence is strongest for combination, targeted, or stimulus-responsive systems, especially PMX/RES liquid crystalline nanoparticles, ELT/RES-NLCs, EGF-DTX/RES lipid–polymer hybrid nanoparticles, and folate-integrated pH-responsive RES lipid–polymer hybrid nanocarriers.

Overall, lipid-based RES systems in lung cancer show a progression from pulmonary-deposition-oriented formulation design to therapeutic co-delivery and targeted or stimulus-responsive antitumor platforms. TRES-NLCs are most relevant to non-invasive pulmonary delivery feasibility; PMX-RSV-LCNPs and ELT/RES-NLCs provide treatment-oriented combination evidence; and EGF- or folate-directed lipid–polymer hybrid systems currently offer the most developed disease-specific evidence for targeted, microenvironment-responsive RES delivery in NSCLC.

Polymeric Nanocarriers

Polymeric micelles provide a core–shell architecture that can solubilize hydrophobic RES within the inner core while allowing surface modification for receptor-associated delivery. A directly lung-cancer-relevant example was reported by Zhao et al¹¹⁰ who developed folic acid-grafted dextran stearate submicron particles loaded with RES for NSCLC therapy. In this system, the hydrophobic stearate component supported RES encapsulation, whereas folic acid modification introduced receptor-associated targeting capacity. The RES-loaded folate-functionalized micelles exhibited controlled drug release and enhanced cellular uptake in A549 cells through folate-associated receptor interactions, together with stronger antitumor activity than non-targeted or free-RES comparators. Thus, this platform provides direct evidence that polymeric micelles can combine RES solubilization, controlled release, and receptor-guided tumor-cell delivery in NSCLC. The general micellar advantages of steric stabilization and improved dispersion remain relevant, but the lung-cancer-specific value of this system derives mainly from the integration of folate-associated uptake with RES delivery rather than from solubilization alone.^111,112

Distinct from ligand-targeted micelles that encapsulate RES as a payload, Yang et al¹¹³ developed a glutathione-responsive poly-resveratrol (PRES) nanoparticle in which RES forms part of the therapeutic polymeric architecture itself. The approximately 93-nm nanoparticles were further used to deliver paclitaxel and were designed to undergo intracellular degradation in the high-glutathione environment of tumor cells. In paclitaxel-resistant A549/PTX cells and corresponding tumor-bearing mice, the PTX@PRES system enhanced antitumor activity and supported reversal of multidrug resistance. This formulation is therefore a redox-responsive polyprodrug/self-assembled nanoparticle rather than a conventional RES-loaded micelle, functioning as an MDR-oriented co-delivery system.

Beyond micellar systems, polymeric RES nanocarriers for lung cancer now encompass conventional cytotoxicity-oriented matrices, inhalable cyclodextrin-complex-loaded nanoparticles, receptor-targeted polymeric delivery systems, gene–drug co-delivery platforms, and immunometabolic nanotherapeutics. An especially lung-adapted polymeric delivery strategy was reported by Wang et al⁵⁸ who incorporated a resveratrol–cyclodextrin complex into inhalable biodegradable nanoparticles for NSCLC therapy. Complexation with sulfobutylether-β-cyclodextrin substantially increased the aqueous solubility of RES, while the nanoparticle formulation exhibited aerosolization characteristics compatible with deposition in the lower respiratory tract. Because this system was evaluated in NSCLC experimental models and showed enhanced anticancer efficacy compared with free RES, it provides direct evidence that route-adapted pulmonary nanodelivery can complement systemic tumor accumulation strategies.

Building on the cyclodextrin–polymeric delivery concept, Wang et al¹¹⁴ subsequently developed transferrin-conjugated PLGA nanoparticles carrying a RES–cyclodextrin complex for receptor-mediated delivery in NSCLC cells. The optimized CD-RES transferrin-targeted nanoparticles exhibited approximately 90% encapsulation efficiency and produced stronger anticancer effects in transferrin-receptor-overexpressing H1299 cells than plain RES or non-targeted nanoparticles. The formulation reduced colony formation and migration, promoted apoptosis, and demonstrated enhanced penetration and growth inhibition in three-dimensional tumor spheroids. Because this evidence remains based on in vitro and spheroid models, it should be presented as an active-targeting advance within polymeric RES nanomedicine rather than as established in vivo tumor-selective therapy.

Gene–drug co-delivery represents an additional extension of polymeric RES nanomedicine in lung cancer. Yao et al¹¹⁵ developed PLGA-PEI nanoparticles co-delivering RES and PTEN siRNA and evaluated the formulation in A549 and cisplatin-resistant A549/T12 lung cancer cells. This study provides proof of concept that RES-containing polymeric nanoparticles can be combined with nucleic-acid payloads in drug-resistant lung cancer models. Because the PTEN-related mechanistic interpretation requires careful alignment with the original experimental design and the established tumor-suppressive role of PTEN, this platform should presently be described conservatively as an exploratory gene–drug co-delivery strategy rather than as a validated resistance-reversal mechanism.^115,116

Polymeric RES nanocarriers in lung cancer have begun to extend beyond direct cytotoxicity and gene co-delivery toward the active reprogramming of antitumor immunity. Jiang and Li¹¹⁷ engineered CD93-targeted RES-loaded PLGA nanoparticles and reported that, in models of immunotherapy-resistant lung cancer, the platform remodeled the metabolism of CD8⁺ tumor-infiltrating T lymphocytes by enhancing apoptosis-inducing factor (AIF)-mediated oxidative phosphorylation, thereby restoring effector competence and overcoming resistance to immune checkpoint blockade. Mechanistically, this metabolic reprogramming was attributed to a CD93–AKT–PAK5–AIF signaling axis and was accompanied by increased oxygen consumption, elevated interferon-γ and granzyme B production, and a reduced proportion of PD-1⁺ and Tim-3⁺ exhausted CD8⁺ T cells. This strategy is conceptually distinct from the tumor-cell-directed chemosensitizing and pro-apoptotic carriers discussed above because it positions RES as a modulator of CD8⁺ T-cell metabolic fitness. However, as this evidence currently derives from a single study, CD93-targeted RES-PLGA nanoparticles should be described as a mechanistically novel proof of concept requiring independent replication before being advanced as immunotherapy-adjuvant candidates in lung cancer.¹¹⁷

Inorganic and Metallic Nanocarriers

Gold NPs (AuNPs) exhibit unique optoelectronic properties, such as surface plasmon resonance, enabling their application in combined photothermal therapy (PTT) and chemotherapy for lung cancer. RES serves dual roles in AuNP synthesis: as a therapeutic payload and as a reducing/capping agent in green synthesis, eliminating toxic chemical reductants.^118–120

The most directly relevant RES–AuNP evidence for lung cancer is provided by Kumar et al¹²¹ who prepared bacterial gold nanoparticles conjugated to RES and evaluated their activity in A549 lung adenocarcinoma cells. The RSV-AuNP formulation demonstrated stronger anticancer activity than free RES in vitro, supporting the use of gold nanoparticles as a nanoscale delivery vehicle capable of improving RES-associated cellular effects in lung cancer cells. However, the currently available lung-cancer-specific evidence for RES–AuNPs remains predominantly in vitro.

Protein- and Polysaccharide-Based Nanocarriers

Protein- and polysaccharide-based carriers provide a natural-macromolecule route for pulmonary RES delivery. Karthikeyan et al¹²² encapsulated RES in gelatin nanoparticles and evaluated the formulation in NCI-H460 NSCLC cells. Compared with free RES, the gelatin nanoparticles produced stronger growth inhibition, disrupted mitochondrial membrane potential, increased intracellular ROS and DNA-damage-associated responses, suppressed constitutive NF-κB activation, and promoted apoptosis, thereby establishing direct in vitro support for protein-based RES nanodelivery in lung cancer. As a polysaccharide-based counterpart, RES-loaded acetalated-dextran nanoparticles inhibited the formation and growth of A549 lung tumor spheroids in a three-dimensional in vitro model through pH-dependent RES release.¹²³ Together, these systems provide complementary in vitro evidence for natural-macromolecule RES carriers in lung cancer, although the spheroid study should not be overstated as in vivo validation and both platforms still require systemic efficacy and safety evaluation.

Comparative Assessment of Nanocarrier Platforms for Lung Cancer

A comparison of lung-cancer-directed RES nanocarriers reveals distinct therapeutic niches that should be interpreted according to both carrier design and evidentiary maturity. Liposomal systems currently provide direct in vivo evidence along two complementary directions: mitochondria-targeted liposomes designed to restore apoptosis in resistant lung cancer cells, and conventional RES liposomes associated with modulation of the TLR4/NLRP3 inflammatory pathway and tumor immune responses. Among lipid-based combination systems, PMX-RSV liquid crystalline nanoparticles provide direct in vitro and in vivo evidence for chemo–herbal co-delivery, ELT/RES nanostructured lipid carriers support targeted-drug/RES synergy in A549 cells. Lipid–polymer hybrid systems add ligand- and stimulus-responsive delivery, with EGF-DTX/RES nanoparticles and folate/pH-responsive RES nanocarriers providing disease-specific in vivo support. In route-oriented terms, lipid-matrix systems such as SLNs/NLCs are most relevant when pulmonary deposition and aerosol compatibility are the dominant design priorities, although the direct aerosolization evidence in the current RES lung-cancer literature is stronger for NLCs than for SLNs. By contrast, polymeric micelles and small targeted polymeric nanoparticles are better suited to improving aqueous dispersion, receptor-guided uptake, and spheroid or stromal penetration, but they do not automatically satisfy inhalation-performance requirements. Therefore, lung-cancer carrier selection should distinguish pulmonary deposition, intratumoral penetration, and systemic MDR-oriented delivery rather than ranking platforms by anticancer potency alone.

Polymeric systems offer broad mechanistic diversity without relying on a single delivery route. The inhalable RES–cyclodextrin biodegradable nanoparticle platform is particularly relevant to lung cancer because it links improved RES solubility with pulmonary deposition and NSCLC-oriented efficacy. Transferrin-conjugated CD-RES PLGA nanoparticles further extend this platform toward receptor-mediated delivery, whereas PTX@PRES nanoparticles address paclitaxel-resistant disease through glutathione-responsive drug release. More recently, CD93-targeted RES-loaded PLGA nanoparticles have introduced an immunometabolic strategy for immunotherapy-resistant lung cancer through modulation of CD8⁺ T-cell metabolic fitness.

In contrast, the current direct lung-cancer evidence for RES-conjugated gold nanoparticles remains primarily limited to in vitro A549-cell studies and does not yet justify positioning this platform as an established photothermal or in vivo theranostic strategy. Overall, the most defensible translational priorities are inhalable RES–cyclodextrin polymeric nanoparticles for local pulmonary delivery, ligand- or stimulus-responsive lipid/hybrid carriers for tumor-directed combination therapy, PTX@PRES nanoparticles for multidrug-resistant disease, and CD93-targeted PLGA nanoparticles for immunotherapy-resistant settings. All of these strategies remain preclinical and require pharmacokinetic, safety, manufacturability, and clinically relevant route-of-administration validation before human application.

Colorectal Cancer

Colorectal cancer (CRC) ranks as the third most frequently diagnosed malignancy and the second leading cause of cancer-related mortality worldwide, with pathogenesis involving dysregulation of the Wnt/β-catenin pathway, chronic inflammation, and oxidative stress.⁵³ RES modulates these oncogenic pathways, suppresses aberrant crypt foci formation, and induces cell cycle arrest.^54,55

However, the clinical translation of orally administered RES in CRC management is impeded by its rapid metabolism, including glucuronidation and sulfation in the intestinal epithelium and liver, as well as degradation by gut microbiota. This extensive first-pass elimination results in sub-therapeutic local and systemic concentrations. Consequently, the development of robust nano-delivery systems capable of protecting the bioactive compound from premature degradation in the harsh GI environment and facilitating its targeted accumulation in tumor tissues is of paramount importance.¹²⁴

CRC occupies a unique position among the malignancies reviewed herein, as the primary tumor is directly accessible via the oral administration route. This anatomical advantage shifts the central nanocarrier design challenge from systemic biodistribution to GI stability and site-specific colonic release. However, for advanced or metastatic CRC, systemic intravenous delivery remains necessary to address disseminated disease. Accordingly, the following subsections evaluate each nanocarrier platform primarily through the lens of its capacity to protect RES through the harsh GI environment while maximizing local drug concentrations at the tumor site. In addition to improving local colonic exposure, recent CRC-directed RES nanocarriers have increasingly moved toward mechanism-oriented combination therapy, including ferroptosis induction, immunogenic cell death, platinum sensitization, stromal modulation, and pH-responsive intracellular release. These developments make CRC one of the most formulation-sensitive indications for RES nanomedicine, but also require careful distinction between oral colon-targeting evidence, in vitro tumor-cell cytotoxicity, and true in vivo antitumor efficacy. The principal oral and targeted nano-delivery strategies for RES in CRC are depicted in Figure 4.

Figure 4.

Integrated oral and targeted resveratrol nanocarrier strategies for colorectal cancer: pH-gated colonic release, mucus-barrier modulation, folate-mediated uptake, apoptosis, and Wnt/β-catenin suppression. This schematic summarizes complementary mechanisms associated with different RES nanocarrier approaches for colorectal cancer (CRC) and does not represent a single carrier system incorporating all modules shown. In the left upper panel, Eudragit S100-coated RES-loaded nanoparticles are depicted as remaining intact under gastric acidic conditions (pH 1.2) and releasing RES after exposure to the higher-pH colonic environment (pH > 7.0). The left lower panel illustrates the steric and interactive components of the intestinal mucus barrier, which can restrict drug transport and epithelial access, whereas RES-loaded nanoparticles are depicted as facilitating localized delivery toward the colorectal tumor compartment. In the right upper panel, folate receptor-targeted RES-loaded nanoparticles are illustrated as binding to folate receptors, undergoing endocytosis, and releasing RES intracellularly, resulting in increased ROS, increased Bax and caspase-9/-3, decreased Bcl-2, and enhanced apoptosis. The lower-right module illustrates inhibition of canonical Wnt/β-catenin signaling, in which enhanced phosphorylation of β-catenin by CK1α/GSK-3β promotes ubiquitin-mediated proteolysis, thereby limiting TCF/LEF-dependent transcription. Solid arrows indicate transport, targeting, endocytosis, release, or signaling progression; dashed arrows indicate schematic movement or proteolytic processing; upward arrows (↑) indicate increased expression, activation, release, or ROS production; downward arrows (↓) indicate reduced expression; inhibitory T-ended lines indicate pathway blockade; red cross symbols indicate impaired passage through the mucus barrier; and the letter P indicates phosphorylation.

Abbreviations: CRC, colorectal cancer; RES, resveratrol.

Lipid-Based Nanocarriers

Liposomal nanoformulations have been widely investigated to augment the stability and bioavailability of RES for CRC therapy. The lipid bilayer structure not only protects hydrophobic RES from gastric acid degradation and enzymatic hydrolysis but also mimics biological membranes, enhancing cellular internalization.

Liposomal RES formulations have been investigated for their capacity to disrupt the stromal compartment of the CRC tumor microenvironment rather than to act as direct cytotoxic agents. In a representative study, Dana et al¹²⁵ encapsulated RES in liposomes (L-RES) prepared by thin-film hydration and demonstrated that, at subtoxic concentrations, L-RES selectively disrupted communications between cancer-associated fibroblasts (CAFs) and HT-29 colorectal carcinoma cells in co-cultured tumor spheroids. Treatment significantly reduced CAF activation markers (α-SMA, IL-6) and attenuated CAF-induced 5-fluorouracil resistance in the spheroid model. This stromal-disrupting strategy is mechanistically distinct from the direct apoptotic targeting pursued by other CRC nanocarrier platforms reviewed below, and underscores the importance of matching nanocarrier design to the specific tumor-microenvironment vulnerability being addressed.

Combination liposomes have further extended CRC-directed RES delivery from stromal modulation to regulated cell death. Jia et al¹²⁶ developed PEG-modified nanoliposomes co-encapsulating rapamycin and RES to promote apoptosis and ferroptosis in colorectal cancer therapy. This design is mechanistically relevant because rapamycin-mediated pathway modulation can be paired with RES-associated oxidative-stress and death-signaling effects within a single lipid carrier. The co-loaded liposomes enhanced antitumor activity compared with single-agent formulations and supported the concept that RES-containing liposomes may be used not only as solubilizing systems but also as combination platforms that coordinate apoptosis- and ferroptosis-associated responses in CRC.

Solid lipid nanoparticles also provide direct colorectal-cancer-specific evidence for RES-containing lipid delivery. Serini et al¹²⁷ developed an omega-3 polyunsaturated fatty acid-loaded, RES-based solid lipid nanoparticle system and evaluated its antineoplastic activity in human colorectal cancer cells in vitro. The formulation reduced tumor-cell growth and invasion-associated behavior, demonstrating a combination lipid strategy in which the nanoparticle matrix contributes an additional bioactive component while RES remains central to the anticancer design. Because omega-3 fatty acids are themselves biologically active, this system should be interpreted as a RES-containing combination nanoplatform rather than as evidence for RES-only SLN monotherapy.

A directly CRC-relevant active-targeting lipid nanoparticle strategy was reported by Senthil Kumar et al¹²⁸ who developed chitosan-coated, folic-acid-conjugated solid lipid nanoparticles co-loaded with trans-resveratrol and ferulic acid (C-RSV-FER-FA-SLNs). The formulation showed favorable stability under acidic conditions, an important property for gastrointestinally relevant delivery, and produced stronger cytotoxicity and apoptosis-associated responses in HT-29 colon cancer cells than the corresponding free RSV/ferulic acid combination. This study provides direct evidence that folate-conjugated RES-containing lipid nanoparticles can enhance anticancer activity in CRC cells.

While liposomal systems demonstrate exceptional efficacy for intravenous targeting of metastatic CRC, their inherent susceptibility to bile salt-mediated destabilization necessitates alternative structural designs for direct oral delivery to primary colonic tumors. These limitations do not diminish the value of lipid-based RES carriers in CRC, but they clarify why structurally robust polymeric and polysaccharide-based systems have been developed for oral colon-targeted delivery, as discussed below.

SLNs provide a structurally stable lipid-based option for CRC-oriented RES delivery, particularly where protection during gastrointestinal transit and sustained colonic release are required. By encapsulating RES within physiological lipid matrices such as stearic acid or glyceryl monostearate, SLNs can reduce premature degradation and improve apparent bioavailability.^127,129 In comparative formulation studies, RES-loaded SLNs prepared by hot homogenization showed spherical morphology, particle sizes around 150 nm, negative zeta potential, and encapsulation efficiencies exceeding 90%.¹³⁰ Simulated gastrointestinal release studies further indicated reduced premature leakage under gastric conditions and more sustained release under colonic pH, supporting their rationale for oral CRC-directed delivery.¹³¹

At the cellular level, RES-SLNs enhanced uptake and antiproliferative activity in HT-29 colorectal adenocarcinoma cells compared with free RES, accompanied by late-stage apoptosis and G0/G1 cell-cycle arrest. Some pharmacokinetic evidence also suggests that oral RES-SLNs may prolong intestinal residence and increase local exposure, which is relevant for CRC therapy.¹³² Nevertheless, CRC-specific evidence for RES-SLNs remains concentrated in formulation stability, cell-based efficacy, apoptosis-related assays, and limited pharmacokinetic evaluation. Additional studies assessing oral biodistribution, colonic retention, tumor-bearing CRC models, and comparison with pH-sensitive polymeric or polysaccharide systems are still needed before SLNs can be ranked as the leading CRC-directed RES platform.

Polymeric Nanocarriers

Polymeric NPs constitute a versatile platform for the oral delivery of RES in CRC management, offering distinct advantages in protecting hydrophobic payloads from the harsh acidic gastric environment and enzymatic degradation in the upper GI tract. To achieve site-specific colon delivery, pH-sensitive polymers, including methacrylic acid copolymers have been extensively employed to coat RES-loaded cores.¹³³ To successfully navigate the harsh GI tract and enhance oral bioavailability, PLGA NPs were surface-functionalized with a pH-responsive anionic methacrylate copolymer (poly(methacrylic acid-co-methyl methacrylate); Eudragit^® S100). The resulting core-shell nanostructures exhibited a pH-dependent release profile: minimal drug leakage occurred at pH 1.2 (simulated gastric fluid), while rapid and sustained release was observed at pH 7.4 (simulated colonic fluid). This release behavior supports localized RES exposure at the intended colonic site while limiting premature gastric leakage.^134,135 An important translational caveat is that the pH-gated logic of this design presupposes a stable colonic luminal pH ≈7.4, whereas inter-individual colonic pH varies between approximately 5.7 and 7.4 even in healthy subjects and is further perturbed in inflammatory bowel disease, advanced colorectal cancer, and antibiotic-altered microbiota states—heterogeneity that can produce premature gastric release or, conversely, incomplete colonic release at the intended site.¹³⁶ To preserve site-specific release fidelity under this physiological variability, dual-trigger architectures combining pH-responsive methacrylate-copolymer outer shells with inner cores cleavable by colonic microbial azoreductases have been advanced as a redundancy mechanism: should either trigger fail in a given patient, the alternate pathway sustains release specificity—an approach with direct precedent in approved azo-prodrugs (sulfasalazine, olsalazine) and one that warrants integration into future colonic RES nanoformulations.¹³⁷

Surface engineering of RES nanocarriers further strengthens their performance against the colonic mucus barrier. Chitosan coating of resveratrol-loaded zein nanoparticles improved gastrointestinal stability, suppressed premature RES release in simulated gastric and intestinal fluids, and enhanced mucin adsorption and mucoadhesion in vitro.¹³⁸ N-trimethyl-chitosan-modified solid lipid nanoparticles increased the oral bioavailability of RES approximately 3.8-fold relative to a free RES suspension in vivo.¹³⁹ These mucoadhesion- and mucus-interaction-tuned surfaces prolong colonic residence and enhance epithelial delivery of RES.

Biologically, these colon-targeted NPs demonstrated enhanced adhesion to inflamed colonic mucosa—a common malignancy precursor—thereby prolonging local residence time. In vitro assays using Caco-2 and HT-29 colorectal adenocarcinoma cells revealed that NPs significantly improved cellular internalization compared to free RES. Mechanistically, efficacy enhancement is attributable to activation of the intrinsic apoptotic pathway—Bax upregulation, Bcl-2 downregulation, and caspase-9/-3 cleavage,^26,28 here initiated by RES-induced ROS after endosomal escape and amplified by the locally elevated intracellular RES that nanoencapsulation delivers. These findings substantiate the potential of pH-responsive polymeric NPs as a robust strategy for oral CRC chemotherapy.¹⁴⁰ Engaging the Wnt/β-catenin axis central to CRC, resveratrol-loaded PLGA nanoparticles (≈178 nm) combined with sunitinib produced synergistic cytotoxicity against HT-29 cells in both two- and three-dimensional cultures,^141,142 confirming that colon-targeted RES nanocarriers can act on this driver pathway.¹⁴³

Importantly, polymeric RES nanoformulation has already demonstrated disease-specific in vivo activity in colorectal cancer. Sudha et al⁵⁵ evaluated nanoformulated RSV in both COLO205-luc xenograft and orthotopic colon-cancer mouse models. Compared with free RSV, the nanoformulation showed greater bioavailability and produced stronger reductions in tumor growth and tumor-associated hemoglobin content, supporting enhanced antitumor and antiangiogenic activity. Because this evidence was generated in both xenograft and orthotopic models, it represents one of the most important in vivo validation points for polymeric RES nanomedicine in colorectal cancer.

Oral residence-time extension represents another CRC-specific formulation strategy. Md et al¹⁴⁴ developed a long-acting oral RES nanocomposite in-situ gelling film for colorectal cancer treatment. In this system, RES-containing nanocomposites were incorporated into an alginate-based film designed to provide sustained release and prolonged local exposure after oral administration. Although this platform remains primarily an in vitro formulation and cytotoxicity study, it is relevant to CRC because it shifts the design goal from systemic circulation to local gastrointestinal retention and extended mucosal exposure.

Beyond single-agent polymeric carriers, recent CRC studies have extended polymeric and stimuli-responsive RES nanoparticles toward combination and alternative cell-death strategies: Li et al¹⁴⁵ constructed pH-sensitive nanoparticles that release RES and trigger immunogenic cell death in colon cancer cells in vitro, and Andishmand et al¹⁴⁶ developed a food-grade pectin–zinc–chitosan–PEG colloidal nanosuspension for colon-targeted RES delivery; the latter is best regarded as delivery-platform feasibility evidence rather than proof of antitumor efficacy.

Polymeric micelles, formed through the self-assembly of amphiphilic block copolymers at concentrations exceeding the critical micelle concentration, constitute a promising approach to enhance the solubility and therapeutic efficacy of RES in CRC management. A key advantage of specific micellar systems—notably those incorporating poloxamers or TPGS—lies in their intrinsic capacity to inhibit the P-gp efflux pump, thereby counteracting MDR prevalent in advanced CRC.¹⁴⁷

Polymeric micelles based on poloxamer block copolymers offer a multifunctional delivery platform for RES in CRC chemotherapy contexts, exploiting two well-established functional advantages: (i) intrinsic inhibition of P-glycoprotein (P-gp)-mediated efflux through membrane-fluidizing interactions of the poly(propylene oxide) blocks with the lipid bilayer—a mechanism documented across diverse poloxamer formulations and tumor models¹⁴⁸—and (ii) the capacity to co-encapsulate RES with cytotoxic chemotherapeutics, leveraging RES as both a chemosensitizer and a cardioprotective antioxidant during anthracycline-based regimens. In an illustrative formulation, Radeva et al¹⁴⁹ developed poloxamer 407/poloxamer 403 mixed micelles (1:1 w/w) co-loaded with doxorubicin and resveratrol via film hydration, achieving a hydrodynamic diameter of approximately 26 nm with encapsulation efficiencies of 83.4% (doxorubicin, sequestered in the PEO shell) and 78% (resveratrol, partitioned into the hydrophobic PPO core). In H9c2 cardioblasts, the double-loaded micelles significantly attenuated doxorubicin-induced cytotoxicity relative to free doxorubicin at equivalent concentrations (IC₅₀ of free doxorubicin ≈ 5 μM in H9c2), while in L5178 lymphoma cells the same formulation enhanced doxorubicin’s antitumor activity—together demonstrating the dual benefit of resveratrol co-delivery in mitigating off-target cardiotoxicity without compromising on-target efficacy.¹⁴⁹ This cardioprotective mechanism is consistent with the earlier proof-of-concept of Cote et al¹⁵⁰ who demonstrated that poloxamer 407 micelles co-loaded with resveratrol and quercetin (mRQ), administered concurrently with doxorubicin, conferred near-complete cardioprotection in tumor-bearing mice while preserving the anticancer efficacy of doxorubicin. Importantly, this cardioprotection paradigm is directly relevant to CRC chemotherapy, where doxorubicin remains a salvage option in advanced/metastatic disease and where 5-fluorouracil and oxaliplatin regimens carry their own cardiovascular safety considerations.

Beyond poloxamer-based platforms, alternative copolymeric micelles have been investigated for the oral delivery of RES, exploiting different design rationales. Kamenova et al¹⁵¹ developed PMAA-b-PCL-b-PMAA triblock copolymeric micelles loaded with resveratrol (≈100 nm; ZP −30 mV; 72% EE), achieving substantially improved aqueous dissolution (~80% release within 24 h at pH 1.2 and 100% at pH 6.8 versus <10% for free RES under the same conditions) and demonstrating that 5 μM micellar RES preserved viability of HT-29 colorectal epithelial cells under inflammatory co-culture stress, whereas free RES at the same concentration provided no protection. This anti-inflammatory protective effect is mechanistically distinct from the chemosensitization-cardioprotection combination of the poloxamer-based platforms above and points toward a complementary chemoprevention application for early-stage or inflammation-driven colorectal carcinogenesis.

Despite these advances in formulation feasibility and chemosensitization-oriented design, single-loaded RES poloxamer-based micelles remain insufficiently validated in MDR colorectal cancer models. Direct evidence is still limited for several key mechanistic questions, including the dominant endocytic uptake pathway, the intracellular concentration of free RES, and whether P-gp suppression is the principal driver of sensitization in resistant CRC cells. Therefore, poloxamer-based RES nanoformulations should be framed as formulation-feasible and mechanistically plausible adjuvant systems rather than fully validated standalone MDR-reversal platforms.

At the same time, the available data should not be dismissed. Reported micelle-treated cells showed increased apoptosis by flow cytometry, supporting restoration of chemosensitivity and activation of mitochondrial cell-death pathways.¹⁵¹ Thus, polymeric micelles remain relevant for CRC because they may combine RES solubilization, improved intracellular drug retention, and chemosensitization, but future studies should confirm these mechanisms using uptake-inhibitor profiling, endolysosomal colocalization, LC-MS/MS-based intracellular free-RES quantification, and P-gp functional assays.

Inorganic and Metallic Nanocarriers

Mesoporous silica NPs (MSNs) have emerged as versatile nanocarriers for CRC therapeutics, characterized by their high specific surface area exceeding 800 m²/g, tunable pore geometry, and facile surface functionalization. These inorganic matrices demonstrate superior efficacy in encapsulating hydrophobic agents such as RES, providing GI stability against enzymatic degradation while achieving high drug loading via physical adsorption within mesopores.¹²⁴

Mesoporous silica nanoparticles (MSNs) provide a high-surface-area, structurally rigid platform that can substantially improve the dissolution rate and intestinal permeability of poorly soluble RES. In a representative formulation study, Juère et al¹⁵² encapsulated RES within MCM-48-type MSNs of 90–300 nm with pore diameters of 3.5–7 nm, demonstrating that the smallest particles (90 nm) significantly enhanced RES permeability through human Caco-2 colon carcinoma monolayers relative to free RES suspensions, an outcome attributed to improved dissolution kinetics and amorphous-state stabilization of the encapsulated payload. This permeability gain provides a rational basis for evaluating MSN-based RES nanocarriers in oral CRC therapy, although direct cytotoxicity data against CRC cell lines from primary engineered RES-MSN platforms remain limited and warrant further investigation.

Mechanistically, intracellular RES release from MSNs was associated with activation of mitochondrial apoptosis, including loss of mitochondrial membrane potential and cytochrome c translocation. These findings support the capacity of MSN-based systems to improve intracellular delivery and antiproliferative activity of RES in colorectal cancer models.¹⁵³ The principal translational headwind for these MSN platforms is the long-term gastrointestinal and systemic fate of non-biodegradable amorphous silica frameworks, which—unlike PLGA or albumin matrices—lack a defined enzymatic clearance pathway and have been associated with hepatic granuloma formation at cumulative doses in rodent models.¹⁵⁴ A direct architectural response that has matured rapidly over the past five years is mesoporous organosilica nanoparticles (MONs) bearing disulfide or tetrasulfide bridges within the silica framework: these retain the high surface area and pore-gating capability of conventional MSNs but undergo GSH-triggered intracellular degradation into clearable silicate fragments at the 2–10 mM cytosolic GSH concentrations characteristic of tumor cells.¹⁵⁵ Adapting this disulfide-bridged organosilica chemistry to RES delivery is a concrete but underexplored route to move MSN platforms toward biodegradable nanocarrier classes with established regulatory precedent.

A newer pH-responsive inorganic strategy was reported by Sun et al¹³³ who prepared tannic-acid-modified resveratrol-loaded ZIF-8 nanoparticles (Res@ZIF-8/TA) for colon-cancer therapy. In colon-cancer cell experiments, this platform promoted apoptosis and inhibited migration and invasion, supporting the use of an acid-responsive metal–organic framework for intracellular RES delivery. This study expands the inorganic CRC evidence base beyond silica- or metal-based carriers by introducing a pH-responsive ZIF-8 architecture; however, because the available evidence remains cell-based, further in vivo evaluation of therapeutic efficacy and material safety is required.

Inorganic CRC nanocarrier evidence is not limited to silica matrices. Kamal et al¹⁵⁶ radiolabeled RES-loaded gold nanoparticles (99mTc-Res-AuNP) and evaluated physiological uptake and retention in colon cancer tissue. This study primarily provides theranostic and biodistribution evidence, with limited relevance as a cytotoxic-efficacy benchmark.

Protein- and Polysaccharide-Based Nanocarriers

Protein-based nanocarriers, particularly those derived from food-grade plant or milk proteins, provide a biocompatible and biodegradable strategy for improving the oral handling of RES in colorectal-cancer-oriented delivery. Their relevance is primarily grounded in the ability of protein matrices to encapsulate hydrophobic stilbenoids, protect RES from premature degradation, and increase intestinal bioaccessibility, rather than in uniformly demonstrated tumor-selective cytotoxicity. Zein-caseinate composite nanoparticles represent one such food-grade platform. Liu et al¹⁵⁷ developed zein-based composite nanoparticles that improved RES bioaccessibility and anti-inflammatory activity, supporting their value for chemoprevention-oriented oral delivery rather than direct cytotoxic chemotherapy. Earlier casein nanoparticle work further demonstrated increased oral RES bioavailability in vivo, providing a pharmacokinetic rationale for protein-based RES carriers.¹⁵⁸ Yi et al¹⁵⁹ subsequently nanoencapsulated RES using pea protein nanofibrils, improving its water solubility, chemical stability, antioxidant activity, and anticancer activity in Caco-2-related evaluation. This study is best grouped with protein-based RES nanocarriers because the delivery matrix is a plant-protein nanofibrillar carrier. Overall, the current protein-based CRC evidence should be interpreted primarily as support for improved oral handling, bioaccessibility, and platform feasibility rather than as definitive proof of tumor-selective cytotoxic efficacy.

Co-delivery nanocarriers further strengthen the therapeutic rationale for RES in colorectal cancer by positioning RES as a chemosensitizing and microenvironment-modulating payload. N,O-carboxymethyl chitosan nanoparticles co-loading oxaliplatin and RES directly address the need to intensify platinum-based chemotherapy while reducing the limitations of free-drug exposure, with in vitro and in vivo evidence supporting stronger anticancer activity than free-drug or single-nanoparticle treatments.¹⁶⁰ A related mucoadhesive thiolated chitosan strategy co-loading α-mangostin and RES extends this logic to an oral colon-oriented platform, where pH-sensitive/mucoadhesive retention and dual phytochemical loading are combined to enhance activity against colon cancer cells.¹⁶¹ These chitosan-derived systems are particularly relevant to CRC because they align with the GI-accessible nature of the primary tumor, where local residence time, mucus interaction, and controlled colonic release may be more important than systemic EPR-dependent accumulation.

More recent chitosan-derived RES nanocarriers further broaden this polysaccharide-based evidence. Şentürk et al¹⁶² developed nicotinic-acid-modified chitosan nanoparticles loaded with RES (nChiNico-RES). In this design, nicotinic acid functionalization was intended to improve chitosan performance under physiological conditions and to enhance the delivery behavior of the RES-loaded carrier. In vitro, nChiNico-RES reduced the viability of HT-29 human colon adenocarcinoma cells more effectively than free RES and RES-loaded unmodified chitosan nanoparticles, supporting this modified chitosan platform as a new polysaccharide-based RES delivery strategy for CRC-relevant cellular models. Earlier RES-loaded ionically cross-linked chitosan-TPP nanoparticles also provide supportive evidence for chitosan-based RES encapsulation and biological activity, although this study should be interpreted mainly as platform-level RES delivery evidence rather than as dedicated CRC therapeutic validation.¹⁶³

Beyond chitosan- and pectin-based oral carriers, protein and inorganic matrices have expanded the CRC RES nanocarrier repertoire. RES-loaded sericin nanoparticles provide a silk-protein platform with high biocompatibility, sustained release, and selective growth inhibition in Caco-2 colorectal adenocarcinoma cells while maintaining low toxicity toward normal fibroblasts.¹⁶⁴ Lipid-core nanocapsules loaded with RES have also been characterized in colon cancer cells, supporting the ability of nanoscale encapsulation to improve the biological activity of RES in HT-29-type cellular models.¹⁶⁵ More recent biogenic silica carriers co-loading curcumin and RES introduce an inorganic, high-surface-area platform for CRC combination phytotherapy, with activity evaluated in HCT-116 and Caco-2 cells.¹⁶⁶ Although these systems remain predominantly preclinical and in vitro, they fill an important material gap between conventional polymeric nanoparticles and newer biomimetic or immune-oriented CRC nanocarriers.

Cyclodextrins (CDs), a class of cyclic oligosaccharides characterized by a hydrophilic exterior and a hydrophobic cavity, have been extensively employed to enhance the aqueous solubility and physicochemical stability of lipophilic phytochemicals via host-guest inclusion complexation. To further optimize their drug delivery potential for CRC, advanced cross-linked systems termed “nanosponges” have been developed, offering superior drug-loading capacity compared to native cyclodextrins and enabling controlled release within the intestinal tract.¹⁶⁷

In a recent study, RES-loaded β-cyclodextrin nanosponges were synthesized utilizing dimethyl carbonate as a cross-linking agent. The resultant nanostructures displayed a spherical morphology with a mean diameter of 185 ± 6.2 nm and a narrow polydispersity index (PDI < 0.2), indicative of a uniform size distribution suitable for oral administration. Encapsulation within the nanosponge matrix markedly enhanced RES’s water solubility (up to a 50-fold increase) and conferred robust protection against photodegradation and oxidative degradation.¹⁶⁸ This enhancement in anticancer activity was ascribed to the solubilizing effect of the cyclodextrin polymer and the sustained release kinetics, which maintained therapeutic concentrations within tumor cells over extended periods.¹⁶⁹ Moreover, RES-loaded nanosponges were demonstrated to induce cell cycle arrest at the G2/M phase and promote apoptotic pathways, underscoring their efficacy as a targeted delivery platform for CRC management.^170–172

Beyond the canonical apoptotic mechanisms, the sustained intracellular release achievable with cyclodextrin nanosponges may prolong inhibition of the Wnt/β-catenin axis—the principal oncogenic driver in sporadic CRC—through the GSK-3β–mediated β-catenin degradation pathway outlined earlier.

Biomimetic and Cell-Derived Nanocarriers

Biomimetic RES nanodelivery is directly supported in colorectal cancer by the study of Zhang et al¹⁷³ who developed a biomimetic nano-delivery system to amplify the ferroptosis-associated anticancer effect of RES. This platform extends RES nanomedicine beyond improved solubility, passive delivery, or conventional apoptosis induction by demonstrating a carrier-enabled strategy centered on regulated iron-dependent cell death. The biomimetic formulation enhanced RES-associated anticancer activity in colorectal-cancer models and supports ferroptosis modulation as an emerging mechanistic direction for RES nanotherapy in this disease. Accordingly, biomimetic RES nanoparticles may be considered an emerging CRC-oriented strategy with direct preclinical support, although further work is required to evaluate biodistribution, ferroptosis selectivity, long-term safety, and translational feasibility.

Comparative Assessment of Nanocarrier Platforms for Colorectal Cancer

The diverse array of nanocarriers evaluated for CRC management reflects the unique therapeutic landscape of this malignancy, where the oral administration route is preferred and the GI tract presents both an opportunity for localized delivery and a formidable barrier to drug stability. Among the seven carrier classes reviewed, a clear functional hierarchy emerges based on the primary delivery challenge being addressed.

For oral colon-targeted delivery—the most clinically relevant administration route for CRC—methacrylate-coated PLGA nanoparticles and SLNs provide particularly rational design logic. Their structural rigidity and pH-gated release profiles effectively protect RES from gastric degradation while ensuring colonic site-specificity. Liposomes, despite their widespread use in other oncological contexts, may be less favorable for oral CRC therapy due to their susceptibility to bile salt-mediated destabilization. Mesoporous silica NPs occupy an intermediate position: their exceptional surface area and tunable pore architecture enable high drug loading and pH-gated release, but concerns regarding the long-term fate of non-biodegradable inorganic matrices in the GI tract remain unresolved.

For intravenous delivery in metastatic CRC, polymeric micelles incorporating poloxamer block copolymers offer a distinct advantage through their dual capacity for solubilization and intrinsic P-gp inhibition, directly addressing the MDR that limits conventional chemotherapy in advanced disease. Protein-based NPs (zein-caseinate) represent a compelling food-grade alternative with inherent mucoadhesive properties, aligning with the growing interest in nutraceutical-based chemoprevention for CRC-susceptible populations. Cyclodextrin nanosponges provide one of the most notable reported improvements in RES aqueous solubility, though their clinical translation is contingent upon demonstrating manufacturing scalability. A key strategic insight from this comparative analysis is that CRC nanocarrier design may need to prioritize GI stability and site-specific release, particularly for oral colon-targeted strategies, while active targeting may remain relevant for metastatic or systemic delivery settings.

Taken together, oral nano-delivery may improve local intestinal exposure and partially mitigate the pharmacokinetic limitations of free RES in preclinical CRC models, making CRC a rational indication for further translational evaluation.

Breast Cancer

Breast cancer persists as the most prevalent malignancy and principal cause of cancer-associated mortality among women globally, with significant epidemiological burden highlighted in recent global cancer statistics.¹⁷⁴ This heterogeneous disease is categorized into distinct molecular subtypes based on the expression profiles of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Among these, triple-negative breast cancer (TNBC), defined by the absence of all three receptors, constitutes the most aggressive subtype with constrained therapeutic alternatives and poor prognosis, as evidenced by contemporary molecular classifications.¹⁷⁵

RES modulates multiple oncogenic pathways in breast cancer, including inhibition of the PI3K/Akt/mTOR axis and Bcl-2 downregulation, which suppress tumor proliferation and induce apoptosis.^176,177 Additionally, RES functions as a phytoestrogen and sensitizes drug-resistant breast cancer cells to conventional chemotherapeutics such as paclitaxel and doxorubicin.¹⁷⁸ However, its clinical translation requires advanced nano-delivery systems to overcome the well-established bioavailability limitations. The molecular heterogeneity of breast cancer—spanning ER/PR/HER2-defined subtypes and the receptor-negative TNBC phenotype—supports the need for a diversified nanocarrier strategy rather than a one-size-fits-all approach. Consequently, this section presents one of the broadest arrays of nanocarrier platforms reviewed herein, progressing from foundational lipid- and polymer-based carriers to inorganic, protein/polysaccharide, and biomimetic systems. This progression is intended to show how increasing architectural complexity may help address different subtype-specific delivery challenges. The advanced nano-delivery strategies for breast cancer therapy using RES are summarized in Figure 5.

Figure 5.

Complementary resveratrol nanocarrier strategies for breast cancer: targeted delivery, EMT and metastasis suppression, multidrug-resistance reversal, and chemotherapy-associated cardioprotection. This schematic integrates representative mechanisms from distinct RES nanocarrier platforms evaluated in breast cancer and does not depict a single formulation possessing all functions shown. In the left panel, PEGylated liposomal co-delivery of RES and doxorubicin (DOX), together with hyaluronic acid (HA)-modified micelle-mediated CD44 targeting, is illustrated as enhancing tumor-associated delivery and cellular uptake. The downstream anti-metastatic response is represented by epithelial–mesenchymal transition (EMT) suppression, characterized by increased E-cadherin and decreased Vimentin, with reduced tumor-cell dissemination. Tumor-cell death and subsequent dendritic-cell/immune-cell engagement are depicted as potential consequences of enhanced targeted delivery. In the right upper panel, RES-containing combination nanocarriers are illustrated as suppressing P-glycoprotein (P-gp)-mediated efflux, thereby improving intracellular retention of co-administered cytotoxic payloads in multidrug-resistant breast cancer cells. In this module, RES is illustrated as reducing chemotherapy-associated myocardial ROS generation and decreasing cardiac injury. Solid arrows indicate delivery, release, targeting, transport, or downstream biological consequences; upward arrows (↑) indicate increased expression or ROS generation; downward arrows (↓) indicate decreased expression, oxidative injury, or tissue damage; red cross or inhibitory blockade symbols indicate suppression of metastatic dissemination or P-gp-mediated drug efflux; and jagged ROS symbols indicate reactive oxygen species generation.

Abbreviations: CD44, cluster of differentiation 44; DOX, doxorubicin; EMT, epithelial–mesenchymal transition; HA, hyaluronic acid; P-gp, P-glycoprotein; RES, resveratrol.

Lipid-Based Nanocarriers

Liposomes have garnered substantial interest in breast cancer pharmacotherapy, not only for their ability to solubilize hydrophobic agents like RES but also for their aptitude in facilitating combinatorial chemotherapy. A critical paradigm in this domain is the co-encapsulation of RES with anthracyclines, such as doxorubicin (DOX), to ameliorate MDR and mitigate chemotherapy-induced cardiotoxicity.¹⁷⁵

In a landmark investigation targeting MDR breast cancer, PEGylated liposomes co-loaded with RES and doxorubicin were engineered via the thin-film hydration method followed by remote loading. The resulting dual-drug liposomes displayed a uniform particle size of 130 ± 4.5 nm and a PDI below 0.2, ensuring stability during systemic circulation. The formulation was designed to release RES rapidly to sensitize the tumor cells, followed by the sustained release of doxorubicin.⁴⁵

In vitro cytotoxicity assays on doxorubicin-resistant MCF-7/ADR cells revealed that RES co-loading significantly lowered the IC₅₀ of doxorubicin.⁴⁵ Mechanistically, RES may contribute to P-gp-associated MDR modulation through effects on drug-efflux activity and MDR1/P-gp-related signaling pathways. These mechanisms may help explain the improved intracellular doxorubicin retention observed with the co-loaded formulation, although the relative contribution of direct P-gp inhibition versus transcriptional regulation should be interpreted according to the assays performed in the cited study.^43,44 This two-pronged chemosensitization accounts for the sustained restoration of doxorubicin intracellular concentrations with the co-loaded formulation.

Furthermore, in vivo studies in tumor-bearing mice demonstrated that RES/DOX co-loaded liposomes produced stronger tumor-growth inhibition while reducing cardiac injury markers such as CK-MB and LDH compared with free doxorubicin treatment.⁴⁵ This cardioprotective effect is consistent with the antioxidant capacity of RES and may involve activation of Nrf2-associated antioxidant defenses in cardiomyocytes, including downstream phase II enzymes such as HO-1, SOD, and NQO1.^179,180 Importantly, this effect should be interpreted in a tissue- and exposure-dependent manner: in tumor cells, RES co-delivery may reinforce doxorubicin-induced cytotoxic stress and MDR modulation, whereas in myocardial tissue it may attenuate doxorubicin-associated oxidative injury. Thus, RES/DOX co-loaded liposomes provide a combination strategy that links tumor chemosensitization with partial cardioprotection, supporting their value as an adjunctive breast-cancer nanoplatform rather than merely as a solubilizing carrier.¹⁸¹

Liposomal RES systems in breast cancer are particularly important for MDR reversal and subtype-adapted combination therapy. PEGylated liposomes co-encapsulating paclitaxel and RES provide a representative MDR-oriented platform, in which simultaneous delivery of a cytotoxic taxane and a P-gp-modulating natural compound improves intracellular drug retention and strengthens in vivo antitumor activity in resistant breast cancer models.¹⁷⁸ RES-loaded peptide/sucrose liposomes further support the therapeutic value of liposomal encapsulation itself, improving the physicochemical handling of RES while producing direct anti-breast cancer activity.¹⁸² More recently, sequential chitosan and hyaluronic-acid/chitosan coating has extended RES liposomes toward CD44-associated active targeting, making HA-CS-coated liposomes conceptually aligned with the HA-mediated breast cancer targeting strategies discussed in this section.¹⁸³ These liposomal platforms therefore cover three complementary functions: co-delivery for MDR reversal, liposomal RES monotherapy, and polysaccharide-coated active targeting.

Peptide-sucrose liposomes provide a better-supported breast-cancer-specific RES lipid formulation than niosomes. Zhao et al¹⁸² developed resveratrol-loaded peptide-sucrose liposomes (PSL@RES) and reported an IC₅₀ of 20.89 μM against MCF-7 breast cancer cells.¹⁸² In vivo, 5 mg/kg PSL@RES produced stronger antitumor activity than 10 mg/kg free RES, while 10 mg/kg PSL@RES was nearly three times more effective than the same dose of free RES in inhibiting tumor growth in the MCF-7-bearing mouse model. Mechanistically, PSL@RES modulated apoptosis-related markers, including p53, Bcl-2, Bax, and caspase-3, supporting enhanced RES-induced apoptotic signaling in breast cancer.

Solid lipid nanoparticles provide an additional directly supported lipid-based RES strategy for breast cancer. Wang et al¹⁸⁴ developed RES-loaded SLNs and evaluated their activity in triple-negative MDA-MB-231 breast cancer cells. Compared with free RES, the formulation more effectively inhibited cell proliferation, promoted apoptosis, increased G0/G1 cell-cycle arrest and suppressed migration and invasion. Mechanistically, RES-SLNs produced stronger modulation of apoptosis- and proliferation-associated proteins, including an increased Bax/Bcl-2 balance together with reduced cyclin D1 and c-Myc expression. This study provides foundational evidence that SLN-mediated RES delivery can enhance multiple antitumor responses in TNBC-like breast cancer cells.

Route-adapted lipid delivery has also been explored for localized breast-tissue exposure. Gadag et al¹⁸⁵ developed RES-loaded nanostructured lipid carriers administered through microneedle arrays for localized breast-cancer therapy. In MDA-MB-231 cells, the formulation enhanced internalization, produced stronger anticancer activity than free RES, and inhibited cell migration. In preclinical pharmacokinetic studies, microneedle-assisted administration increased systemic exposure parameters and promoted higher RES localization in breast tissue compared with orally administered free RES. This platform broadens breast-cancer RES nanodelivery beyond intravenous systemic targeting toward minimally invasive, locally directed lipid-based administration.

Polymeric Nanocarriers

Polymeric NPs have been extensively engineered to enhance the systemic stability and tumor-targeting capability of RES in breast cancer therapy. PLGA remains a widely used polymer because of its biocompatibility and extensive precedent in FDA-approved drug products. Zhao et al¹⁸⁶ developed albumin-stabilized nanoparticles co-delivering paclitaxel and RES; in breast cancer cells these particles enhanced cytotoxicity relative to the free-drug combination, with mechanistic studies indicating G0/G1-phase cell-cycle arrest and apoptosis induction through caspase-3/9 activation.

To overcome MDR, co-delivery systems have been developed. In vivo studies in tumor-bearing mice showed co-loaded NPs achieved approximately 75% tumor inhibition versus single-drug formulations, highlighting their combinatorial therapeutic potential.⁷⁰

A distinct polymeric combination strategy was developed by Al-Jubori et al¹⁷⁶ who constructed layer-by-layer nanoparticles for the co-delivery of tamoxifen and RES in the context of potential triple-negative breast cancer therapy. This design is relevant because it incorporates an endocrine-modulating agent and RES within a multilayer nanostructure intended to coordinate delivery and improve anticancer activity. Unlike single-payload RES polymeric nanoparticles, the layer-by-layer system expands the breast-cancer evidence base toward dual-drug nanotherapy and should be positioned as an early but directly relevant combination platform for aggressive breast-cancer phenotypes.

Chitosan-based RES nanoformulations also broaden the mechanistic spectrum of breast cancer delivery. In invasive MDA-MB-231 cells, RES nanoformulation has been associated with autophagy-related growth inhibition, including modulation of Beclin-1, ATG5, ATG7, LC3A, and P62 expression.¹⁸⁷ This autophagy-oriented mechanism complements the apoptosis, EMT suppression, MDR reversal, and oxidative-stress modulation emphasized elsewhere in this section, and is especially relevant to TNBC-like cellular contexts where non-apoptotic death pathways may contribute to therapeutic response.

More recent evidence has examined RES-loaded poly(ε-caprolactone)-based polymeric nanoparticles with or without D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) in breast cancer models. Cavalcante de Freitas et al¹⁸⁸ evaluated these formulations in 4T1 breast cancer cells and in vivo tumor-bearing mice. Notably, the polymeric nanoparticle formulation without TPGS exhibited stronger in vitro cytotoxicity and superior in vivo antitumor performance than the TPGS-containing formulation, whereas biochemical evaluation indicated a possible hepatotoxicity signal associated with the TPGS-containing system. Accordingly, this study supports PCL-based polymeric RES nanoparticles as a breast-cancer-directed platform, but it does not demonstrate an advantage of TPGS modification and should not be classified as evidence for RES-loaded lipid–polymer hybrid nanoparticles.

Polymeric micelles, formed through the self-assembly of amphiphilic block copolymers, represent a pragmatic strategy for solubilizing RES and enhancing its accumulation in breast tumors via passive and active targeting mechanisms.¹⁸⁹ An efficacious approach involves employing hyaluronic acid (HA) as the hydrophilic shell material, capitalizing on its role as a natural ligand for the CD44 receptor, which is frequently overexpressed on breast cancer stem-like cells (BCSCs) and TNBC cells.

Given the overexpression of CD44 on aggressive breast cancer stem-like cells, engineering HA-conjugated polymeric micelles has proven to be an effective strategy to actively direct RES accumulation. This formulation exhibited a compact spherical morphology with a mean hydrodynamic diameter of 65 ± 3.1 nm and a negative ZP (−18.5 mV), properties that facilitate deep tumor penetration and reduce systemic clearance.^190,191

In vitro uptake assays confirmed that HA-functionalized micelles were internalized by MDA-MB-231 cells more efficiently than non-targeted micelles, consistent with CD44-associated uptake.¹⁹² The formulation also affected metastasis-related phenotypes: molecular analysis showed increased E-cadherin and decreased Vimentin and N-cadherin, indicating EMT-marker modulation. Because the precise causal sequence among Snail-, Slug-, Twist-, SIRT1-, or β-catenin-associated pathways was not fully resolved in the corresponding nanocarrier model, these effects should be described as being accompanied by EMT-marker changes rather than as definitive proof of a single EMT-reversal pathway.

In orthotopic breast tumor models, HA-targeted micelles suppressed primary tumor growth and reduced lung metastasis incidence, supporting their relevance for advanced or metastatic breast cancer models.^193,194 Their compact size of approximately 65 nm, negative surface charge, and HA-mediated targeting may also favor interstitial diffusion and CD44-directed uptake in dense TNBC stroma.

Nanogels, defined as sub-micron-sized hydrogel particles formed by physically or chemically cross-linked polymeric networks, constitute a versatile delivery platform for RES encapsulation. Their three-dimensional architecture integrates the high hydration capacity and biocompatibility of hydrogels with the colloidal stability characteristic of NPs, thereby enhancing drug loading efficiency and enabling stimuli-responsive release kinetics.¹⁹⁵

In vitro, RES-loaded pH-responsive nanogels enhanced antiproliferative efficacy over free RES under acidic conditions, an effect best attributed to pH-triggered release and increased cell-associated RES exposure rather than to a confirmed proton-sponge endosomal-escape route, which would require endolysosomal colocalization or intracellular free-RES quantification to establish. The cationic surface likely promotes cell association through electrostatic interaction with the plasma membrane, but it may also increase nonspecific protein adsorption and MPS sequestration after systemic dosing, making such nanogels better suited to locoregional or carefully optimized tumor-targeted delivery than to unqualified systemic TNBC use.^195,196

Inorganic and Metallic Nanocarriers

Gold NPs (AuNPs) have emerged as a versatile platform for breast cancer theranostics due to their unique optoelectronic properties, particularly surface plasmon resonance (SPR), which enables applications in PTT.⁹² A prominent advancement in nanomedicine is the biogenic (“green”) synthesis of AuNPs, where RES serves as both a reducing agent—converting Au(III) to Au(0)—and a capping agent that stabilizes the NPs while preserving its own pharmacological activity.^197,198

In a representative eco-friendly synthesis, RES-capped gold NPs (RES-AuNPs) were fabricated without toxic surfactants, yielding monodisperse spherical structures with an average diameter of 20 ± 2.5 nm and a characteristic SPR absorption peak at 535 nm.¹⁹⁹ These NPs demonstrated stability across physiological pH ranges, mitigating aggregation in biological fluids.

Therapeutic evaluation against triple-negative MDA-MB-231 breast cancer cells revealed that RES-AuNPs exhibited intrinsic cytotoxicity via RES release. However, efficacy was significantly enhanced under near-infrared (NIR) laser irradiation.²⁰⁰ The photothermal transduction of the gold core induced localized hyperthermia, elevating intracellular temperatures to levels causing irreversible cellular damage. This combinatorial approach of RES-mediated chemotherapy and photothermal ablation yielded synergistic effects, reducing cell viability to below 15% under laser exposure, compared to approximately 60% with RES-AuNPs alone.²⁰¹ Mechanistically, NIR irradiation drives surface plasmon resonance–mediated photothermal transduction and mitochondrial ROS generation, which amplifies RES-mediated intrinsic apoptosis (Bax↑, Bcl-2↓, caspase-9/3 activation) and eliminates both treatment-sensitive and resistant cells within the irradiated volume. Breast-cancer RES-MSN evidence should also be explicitly acknowledged. Gu et al²⁰² constructed RES-modified mesoporous silica nanoparticles and reported inhibition of MCF-7 proliferation, migration, and invasion with in vivo tumor-growth suppression, while Li et al²⁰³ used peptide-transferrin-targeted MSN-RES to enhance targeted delivery and apoptosis induction in MCF-7 cells. These studies complement the albumin, micelle, liposomal, and exosome platforms by adding receptor-targeted inorganic carriers to the breast-cancer evidence base.

RES-loaded silver nanoparticles have recently been evaluated in MCF-7 and MDA-MB-231 breast cancer cells, where the combined metal-payload system altered viability, apoptosis, necrosis, and cell-cycle distribution.²⁰⁴ Because AgNPs may contribute independent cytotoxic and oxidative effects, these data are most appropriately interpreted as a metal-assisted RES nanoplatform rather than as evidence of RES-specific activity alone. Earlier halloysite clay nanotubes loaded with RES provide a mineral nanotube-based delivery precedent for cancer cells, supporting sustained release and cellular delivery of RES from a non-polymeric tubular scaffold.²⁰⁵ Together, AgNPs and halloysite nanotubes broaden the inorganic carrier category, but their translational positioning should remain more cautious than biodegradable lipid, polymeric, albumin, or exosome-based systems.

Protein- and Polysaccharide-Based Nanocarriers

Albumin-based nanocarriers, predominantly formulated from Human Serum Albumin (HSA) or Bovine Serum Albumin (BSA), represent a clinically familiar protein-carrier platform with precedent in oncology drug delivery. Their rationale includes favorable biocompatibility and possible albumin-associated tumor transport mechanisms, including gp60- and SPARC-related pathways, although these mechanisms should not be assumed for each RES-albumin formulation without direct validation. Specifically, albumin engages the gp60 receptor (albondin) on endothelial cells, facilitating transcytosis across vascular walls, and subsequently accumulates in tumor interstitium via binding to SPARC (Secreted Protein Acidic and Rich in Cysteine)—a matricellular protein frequently overexpressed in invasive breast carcinomas.^206,207

Building upon the clinical success of albumin-bound taxanes, RES-loaded HSA NPs were fabricated through a desolvation technique devoid of toxic cross-linkers. The resulting NPs exhibited spherical morphology with a mean diameter of 135 ± 4.2 nm, optimal for exploiting the EPR effect, and a ZP of −25.1 mV, indicative of colloidal stability. EE exceeded 88%, attributed to hydrophobic binding pockets within the albumin tertiary structure.²⁰⁸

Therapeutic efficacy data for RES-loaded albumin nanoparticles support albumin as a feasible RES carrier platform, particularly because albumin binding can improve aqueous compatibility, prolong circulation, and enhance tumor exposure in preclinical models.²⁰⁸ In breast cancer, the rationale for albumin-based delivery is further supported by the clinical familiarity of albumin-bound nanomedicines and by the broader literature linking albumin transport to gp60- and SPARC-associated pathways.²⁰⁷ However, the available RES-HSA evidence should not be interpreted as direct confirmation of gp60/SPARC-mediated uptake in TNBC unless gp60/SPARC blocking, caveolae-inhibition, endothelial-transcytosis assays, or quantitative intracellular free-RES measurements were performed in the cited study. Accordingly, albumin-based RES delivery should be presented as a clinically familiar protein-carrier strategy with plausible SPARC/gp60 relevance, while the exact cellular uptake route and contribution of transcytosis require direct validation.

Protein-based breast cancer nanocarriers should also include casein micellar systems. Phytosomal bilayer-enveloped casein micelles co-delivering monascus yellow pigments and RES provide a multireservoir protein-based carrier that connects RES delivery with combination phytotherapy in breast cancer.²⁰⁹ This casein platform is mechanistically distinct from albumin nanoparticles and zein nanocapsules: rather than relying primarily on SPARC-mediated albumin transcytosis or zein-based oral protection, it uses casein micellar assembly and phytosomal bilayer engineering to accommodate multiple hydrophobic natural products within a biocompatible matrix. This casein platform therefore broadens the protein-based RES delivery landscape in breast cancer.

Zein- and chitosan-based carriers further expand the protein- and polysaccharide-based RES evidence in breast cancer. Elzoghby et al²¹⁰ developed shell-crosslinked zein nanocapsules for oral co-delivery of exemestane and RES, providing a protein-based combination platform designed to improve oral delivery and endocrine-therapy-associated antitumor efficacy in breast cancer. Chitosan-based RES systems provide a complementary polysaccharide strategy. Bozorgi et al¹⁷⁷ evaluated a chitosan/RES polymeric nanocomplex against triple-negative breast cancer cells and showed enhanced in vitro anticancer activity compared with free RES, supporting chitosan complexation as a TNBC-relevant RES delivery approach. Sericin-based nanocarriers also broaden this category: Aghaz et al¹⁹⁶ developed pH-responsive sericin nanocarriers co-delivering RES and melatonin and demonstrated inhibition of MCF-7 breast cancer cell proliferation under tumor-relevant pH conditions. More recently, Hussein et al²¹¹ reported RES-chitosan nanoparticles as a radiosensitizing platform in a DMBA-induced breast cancer mouse model, where combination with γ-irradiation reduced tumor burden and modulated oxidative-stress, immune, and p53/survivin/STAT3-associated markers. Together, these studies indicate that protein- and polysaccharide-based RES nanocarriers in breast cancer extend beyond albumin and casein systems to include zein, chitosan, and sericin platforms, although most evidence remains preclinical and should be interpreted according to whether RES is used as a monotherapy payload, a co-delivered sensitizer, or a radiosensitizing adjunct.

Biomimetic and Cell-Derived Nanocarriers

While protein- and polysaccharide-based systems improve biocompatibility and oral or systemic handling, biomimetic carriers introduce an additional layer of biological functionality by using naturally derived vesicular membranes to influence tissue distribution and cellular uptake.

Milk-derived exosomes provide directly relevant biomimetic evidence for RES delivery in breast cancer. González-Sarrías et al²¹² showed that passive incubation enabled the loading of RES into milk-derived exosomes and that EXO-RSV delivered free RES to mammary tissue in mice, whereas free RES was not detected in the same way. At nanomolar concentrations, EXO-RSV exerted antiproliferative effects in MCF-7 and MDA-MB-231 breast cancer cells while showing minimal effects on non-tumorigenic MCF-10A cells. In vitro evaluations using paclitaxel-resistant MCF-7 breast cancer cells suggested that exosomal RES formulations may reduce ABC transporter-mediated efflux limitations and improve intracellular RES delivery. The biomimetic lipid bilayer of milk-derived exosomes may facilitate efficient cellular uptake, but the relative contributions of membrane fusion, clathrin-mediated endocytosis, and other uptake pathways should be interpreted cautiously. Therefore, milk-derived exosomes should be described as biomimetic carriers that enhance RES tissue delivery and intracellular availability, rather than as systems conclusively proven to bypass P-gp or avoid endolysosomal trafficking.²¹² In the reported tumor-bearing mouse model, exosome-associated RES delivery reduced tumor burden and was associated with improved survival outcomes, supporting milk-derived exosomes as a promising biomimetic delivery strategy that still requires further validation.^213,214

Comparative Assessment of Nanocarrier Platforms for Breast Cancer

Breast cancer presents one of the most diverse preclinical nanocarrier evaluation landscapes among the malignancies reviewed, reflecting both the heterogeneity of its molecular subtypes and the multiplicity of therapeutic challenges it poses. Foundational carriers—including PLGA polymeric NPs and liposomes—provide relatively well-characterized platforms with favorable formulation experience and documented encapsulation capacity. Among these, liposomes can support co-delivery strategies, with reported effects on P-gp-associated MDR and oxidative-stress-related cardioprotection in selected models.

Advanced targeting platforms—including HA-modified micelles and albumin-based NPs—provide additional architectural functions beyond single-component systems. HA-micelles introduce CD44-associated targeting and have shown anti-migratory or anti-metastatic activity accompanied by EMT-related marker modulation in preclinical models—a critical endpoint for aggressive breast cancer subtypes. Albumin-based nanoparticles may benefit from albumin-related tumor transport mechanisms and from the regulatory precedent of albumin-bound paclitaxel; however, this precedent informs rather than eliminates the need for RES-HSA-specific efficacy, safety, and manufacturing validation.

Next-generation biomimetic systems, particularly milk-derived exosomes, may improve biocompatibility, tissue delivery, and intracellular RES availability, but their uptake routes, MDR-related mechanisms, scalable manufacturing, and quality control remain incompletely defined. The reported reduction in tumor burden and improved survival outcomes support their promise, but this evidence should still be interpreted as early-stage biomimetic validation rather than clinical readiness.

Collectively, breast-cancer carrier selection should be subtype- and purpose-guided. Co-loaded liposomes are most relevant to MDR-associated combination therapy and doxorubicin cardioprotection; HA-modified micelles are better aligned with CD44-associated uptake, EMT-marker modulation, and metastasis-oriented models; albumin-based systems are more relevant to systemic delivery and formulation stability; and milk-derived exosomes represent an exploratory biomimetic strategy for improving tissue delivery and intracellular RES availability.

Additional breast-cancer studies indicate that RES nanomedicine development is expanding beyond exosomes toward stimuli-responsive and food-grade protein-based carriers. Antoniraj et al²¹⁵ designed a redox-responsive disulfide-containing RES nanocarrier and evaluated its anticancer activity in MDA-MB-231 cells, providing in vitro support for glutathione-responsive RES release in TNBC-relevant models. In parallel, Shi et al²¹⁶ reported zein/sodium hyaluronate nanoparticles loaded with RES, demonstrating antioxidant and antitumor activity in vitro. These studies complement the exosome-based evidence by highlighting two distinct design logics—redox-triggered intracellular release and biocompatible protein/polysaccharide encapsulation—although both should be framed as early preclinical evidence rather than clinical efficacy data.

Overall, breast cancer has one of the broadest preclinical evidence bases for RES nanoformulations among the malignancies reviewed, with multiple carrier classes reporting improved cytotoxicity, MDR-related modulation, or anti-migratory/anti-metastatic effects in selected experimental models. The availability of clinically validated carrier technologies (eg, albumin NPs building on established albumin-nanoparticle clinical precedent) and well-characterized molecular targets (CD44, SPARC, HER2) make breast cancer a comparatively mature preclinical setting for prioritizing further pharmacokinetic, safety, and efficacy validation of selected RES nanomedicine candidates. Table 3 summarizes representative RES-loaded nanoformulations evaluated in prostate, lung, colorectal, and breast cancer models.

Table 3.

Summary of Representative RES-Loaded Nanoformulations Evaluated in Prostate, Lung, Colorectal, and Breast Cancer Models

Nanoformulation	Model/Cell Line	Cancer (Subtype)	Evidence	Key Physicochemical/ Design Features	PK/Biodistribution	Outcomes and Mechanisms	Ref.
Curcumin + RES liposomes	PTEN-knockout prostate cancer model	Prostate	In vivo	Liposomal phytochemical co-encapsulation	Tumor prevention model; detailed PK not central	Reduced prostate cancer incidence; chemopreventive co-delivery proof of concept	[78]
RES-loaded SLNs	Prostate biodistribution model	Prostate	In vivo / PK	Lipid matrix for RES	Prolonged circulation and enhanced prostate biodistribution	Exposure-optimizing lipid carrier rather than RES monotherapy efficacy benchmark	[79]
Docetaxel + RES liposomes	Prostate cancer models	Prostate	In vitro + in vivo	Co-loaded liposomes	Systemic co-delivery; quantitative PK not detailed in table source	Docetaxel-associated chemosensitization and synergistic antitumor effect	[80]
PCL + PLGA-PEG RES NPs	DU-145, PC-3, LNCaP	Prostate	In vitro	Nanoprecipitation; fluorescently labeled NPs	Not reported (in vitro only)	Confocal-confirmed uptake; improved antiproliferative activity vs free RES	[81]
RES-loaded PLGA NPs	Prostate cancer cells	Prostate	In vitro	PLGA matrix	Not reported (in vitro only)	Programmed cell death and G1/S cell-cycle arrest	[82]
FA-conjugated PBM NPs (RES ± DTX)	PC3-R docetaxel-resistant cells	Prostate	In vitro	Planetary ball-milled; folate receptor targeting	Not reported (in vitro only)	Cytotoxic RES ~3 μM; FA-RES+DTX apoptosis 65.9%; NF-κB/COX-2/Bcl-2/survivin decreased, BAX/BAK increased	[89]
Folate-chitosan RES-PLGA NPs (Res-PCF)	PC-3	Prostate	In vitro	FA-chitosan surface; IC50 ~51 μg/mL at 48 h	Not reported (in vitro only)	Time-dependent cytotoxicity, apoptosis-gene modulation, ROS generation; sparing of non-malignant cells reported	[90]
pHEMA-chitosan RES nanotherapeutic	PC-3	Prostate	In vitro	pHEMA nanosystem with chitosan surface modification	Not reported (in vitro only)	Material-platform feasibility and cytotoxicity against PC-3 cells	[91]
Res-AuNPs (green synthesis)	PC-3	Prostate	In vitro	RES corona; gold-ion reduction	Not reported (in vitro only)	Higher RES corona associated with improved uptake and anticancer activity	[92]
RESV–198AuNPs (radioactive)	PC-3 xenograft (SCID mice)	Prostate	In vivo	Radioactive gold; intratumoral administration	>85% injected dose retained intratumorally up to 24 h	Local theranostic treatment; >10-fold tumor-volume reduction by week 4 vs saline	[93]
Res-PdNPs	PC-3; PC-3 xenograft (SCID mice)	Prostate	In vitro + in vivo	Palladium NPs; TEM core 24 ± 3 nm; ZP −40 ± 3 mV	IV dosing; systemic in vivo efficacy	Laminin-receptor-associated uptake; NF-κB/macrophage/angiogenesis-related effects; tumor volume 0.06 ± 0.02 cm3 vs 0.37 ± 0.05 cm3 control	[94]
PO3-MSN-RES	PC3 incl. hypoxic docetaxel-resistant cells	Prostate	In vitro	~60 nm phosphonate-functionalized MSN; ~50% release/12 h	Controlled in vitro release; no systemic PK	IC50 14.86 to 7.15 μM; controlled release; preserves docetaxel chemosensitization	[95]
β-CD nanosponges (RES/OXY)	DU-145, PC-3	Prostate	In vitro	CDI-crosslinked; 200–250 nm; 1:4 drug: polymer	Improved solubility/photostability; no systemic PK	2–3× photoprotection; concentration-dependent viability reduction; blank nanosponges non-toxic	[96,97]
Chitosan/alginate-coated RES-PLGA NPs	Formulation-level prostate-relevant delivery	Prostate	Formulation / in vitro	Cationic chitosan or anionic alginate coating	Controlled release and light protection	Improved encapsulation, controlled release, and photoprotection of RES	[98]
Alginate NPs (curcumin + RES)	DU145	Prostate	In vitro	Polysaccharide co-delivery	Not reported (in vitro only)	Feasibility of alginate-based RES/curcumin combination delivery	[99]
Mitochondria-targeted RES liposomes (DQA-PEG-DSPE)	A549, A549/cDDP xenograft	Lung (NSCLC resistant)	In vitro + in vivo	~70 nm; dequalinium-modified mitochondrial targeting	In vivo efficacy; quantitative PK not detailed	ΔΨm dissipation and mitochondrial apoptosis in resistant lung cancer models	[101]
RES liposomes targeting TLR4/NLRP3	In vivo lung cancer model	Lung	In vivo	Liposomal RES	In vivo activity; quantitative PK not reported	Alleviated progression via TLR4/NLRP3 inflammasome modulation and enhanced antitumor immunity	[102]
TRES-NLCs for pulmonary delivery	Pulmonary formulation/deposition models	Lung delivery	Formulation	Particle size <145 nm; EE >96%; nebulizer-compatible aerosol properties	Pulmonary-deposition feasibility rather than tumor PK	Non-invasive pulmonary RES delivery feasibility; not direct antitumor efficacy	[103,104]
PMX-RSV-LCNPs	A549; urethane-induced lung cancer-bearing mice	Lung	In vitro + in vivo	Ion-paired liquid-crystalline NPs co-delivering pemetrexed + RES	In vivo lung-burden evaluation; quantitative PK not detailed	Enhanced uptake/cytotoxicity; tumor burden and VEGF decreased, caspase-3 increased; improved histology/safety	[105]
ELT/RES-NLCs	A549	Lung (NSCLC)	In vitro	Erlotinib + RES nanostructured lipid carriers; ~97.5 nm	Not reported (in vitro only)	Reduced viability; apoptosis and G2/M arrest; BAX/p53/caspase-3/9 increased, survivin/Bcl-2 decreased	[106]
EGF-DTX/RES ROS-responsive LPHNPs	NSCLC models	Lung (NSCLC)	In vitro + in vivo	EGF-conjugated; ROS-responsive; DTX + RES co-encapsulation	In vivo antitumor activity; quantitative PK not reported	EGFR-associated delivery, ROS-triggered release, synergistic DTX/RES activity, reduced systemic toxicity	[107]
FOL-RSV-LPHNCs	A549; A549 xenograft	Lung (NSCLC)	In vitro + in vivo	Folate-integrated pH-responsive hybrid; ~248 nm; EE ~94%	Prolonged systemic exposure vs free RES	Selective internalization; acidic release; enhanced activity and tumor growth suppression	[108]
RES-SLNs (stearic acid/lecithin)	Lung formulation studies	Lung (NSCLC-oriented)	Formulation	100–200 nm; negative ZP; EE >85%	Improved oral bioavailability/sustained release (not lung-tumor PK)	Photostability and sustained release; tumor-volume data insufficient	[109]
FA-grafted dextran stearate RES particles	A549	Lung (NSCLC)	In vitro	Folate-functionalized micellar/submicron particles	Not reported (in vitro only)	Controlled release; folate-associated uptake; stronger activity than non-targeted/free RES	[110]
PTX@PRES GSH-responsive poly-resveratrol NPs	A549/PTX; resistant tumor-bearing mice	Lung (MDR)	In vitro + in vivo	~93 nm redox-degradable PRES polyprodrug; PTX co-delivery	Designed for circulation stability and intracellular GSH-triggered degradation	Reversed MDR; enhanced antitumor activity in resistant lung cancer	[113]
RES–cyclodextrin complex-loaded inhalable biodegradable NPs	NSCLC experimental models	Lung (NSCLC)	In vitro / 3D / delivery	SBE-β-CD complex plus biodegradable inhalable particles	Pulmonary deposition-compatible; no systemic PK	Improved RES solubility and anticancer efficacy vs free RES	[58]
Transferrin-conjugated CD-RES PLGA NPs	H1299; 3D tumor spheroids	Lung (NSCLC)	In vitro + spheroid	~90% EE; transferrin receptor-mediated delivery	Not reported (in vitro/spheroid only)	Enhanced penetration, apoptosis, migration/colony suppression; stronger effects than non-targeted NPs	[114]
PLGA-PEI RES + PTEN siRNA NPs	A549, A549/T12 cisplatin-resistant cells	Lung (resistant)	In vitro	Cationic PLGA-PEI gene–drug co-delivery	Not reported (in vitro only)	Exploratory gene–drug co-delivery; enhanced cytotoxicity vs drug-only strategy	[115,116]
CD93-targeted RES-PLGA NPs	Immunotherapy-resistant lung cancer; CD8+ TILs	Lung (NSCLC)	In vitro + in vivo	CD93-targeted PLGA	In vivo activity; quantitative PK not reported	Remodeled CD8+ T-cell metabolism via AIF-mediated OXPHOS; improved ICB response	[117]
Bacterial RSV-AuNPs	A549	Lung	In vitro	Bacterial gold NPs conjugated to RES	Not reported (in vitro only)	Stronger anticancer activity than free RES; current direct lung evidence remains predominantly in vitro	[121]
RES-loaded gelatin NPs	NCI-H460	Lung (NSCLC)	In vitro	Gelatin nanoparticles	Not reported (in vitro only)	Growth inhibition; ΔΨm disruption; ROS/DNA-damage responses; NF-κB suppression; apoptosis	[122]
RES-loaded acetalated-dextran NPs	A549 3D lung tumor spheroids	Lung	In vitro (3D)	pH-dependent acetalated dextran NPs	Not reported (3D in vitro only)	Inhibited spheroid formation and growth via pH-dependent release	[123]
Liposomal RES (L-RES)	HT-29 + CAF co-culture spheroids	Colorectal	In vitro / spheroid	Thin-film hydration liposomes	Not reported (spheroid only)	Disrupted CAF–tumor crosstalk; α-SMA/IL-6 decreased; attenuated 5-FU resistance	[125]
Rapamycin/RES PEG-modified nanoliposomes	CRC therapy models	Colorectal	In vitro + in vivo	Co-loaded nanoliposomes	In vivo antitumor activity; quantitative PK not detailed	Coordinated apoptosis and ferroptosis; stronger activity than single agents	[126]
C-RSV-FER-FA-SLNs	HT-29	Colorectal	In vitro	Chitosan-coated, folate-conjugated SLNs co-loaded with trans-RES and ferulic acid	Acidic stability; no systemic PK	Enhanced cytotoxicity and apoptosis vs free drug combination	[127]
Omega-3 PUFA/RES-based SLNs	Human CRC cells	Colorectal	In vitro	Bioactive lipid matrix with RES	Not reported (in vitro only)	Reduced growth and invasion-associated behavior; RES-containing combination lipid platform	[128]
RES-SLNs/smart lipids	HT-29; oral PK-oriented evidence	Colorectal	In vitro + PK evidence	~150 nm; negative ZP; EE >90%	Prolonged intestinal residence/elevated local exposure suggested	Sustained colonic release; apoptosis and G0/G1 arrest; further tumor-bearing validation needed	[128–132]
Eudragit S100-coated RES-PLGA NPs	Caco-2, HT-29/colon-targeting models	Colorectal	In vitro/ formulation	pH-responsive methacrylate shell	pH-dependent release; no in vivo tumor PK	Minimal gastric leakage; colonic release logic; physiological pH variability remains a caveat	[133–137]
Nanoformulated RSV	COLO205-luc xenograft; orthotopic colon-cancer mice	Colorectal	In vivo	Nanoformulated RSV; enhanced bioavailability versus free RSV	Improved bioavailability; tumor-associated exposure inferred from efficacy model	Reduced tumor growth and tumor-associated hemoglobin; antiangiogenic activity versus free RSV	[55]
RES-loaded polymeric NPs + sunitinib	HT-29 2D/3D colorectal cancer models	Colorectal	In vitro/3D	Polymeric combination nanoparticles	Not reported (2D/3D in vitro only)	Synergistic cytotoxicity with sunitinib in HT-29 2D/3D cultures; Wnt/β-catenin-related rationale	[141,142]
RES nanocomposite in-situ gelling film	Oral long-acting CRC delivery model	Colorectal	Formulation/in vitro	Oral long-acting nanocomposite gel film	Local oral/GI delivery focus	Sustained oral delivery concept for CRC	[144]
pH-sensitive RES NPs for ICD	Colon cancer cells	Colorectal	In vitro	pH-sensitive RES release	Not reported (in vitro only)	Triggered immunogenic cell death-associated responses	[145]
Pectin-zinc-chitosan-PEG RES nanosuspension	Colon-targeting model	Colorectal	Formulation	Food-grade colloidal nanosuspension	Colon-targeting delivery focus	Mucoadhesive/colon-oriented RES delivery feasibility	[146]
RES-containing polymeric micelles	Lymphoma/CRC-relevant co-delivery; oral micelle models	Colorectal/ MDR-oriented	In vitro + in vivo (selected)	Polymeric micelles; RES with DOX/quercetin; oral copolymer micelles	Variable; cardioprotection and oral delivery evidence	Low cardiac toxicity, enhanced cytotoxicity, and oral micellar RES delivery rationale	[147–151]
RES-MSNs/ degradable MON rationale	CRC cells	Colorectal	In vitro	Mesoporous silica delivery	Not reported (in vitro only)	Intracellular release and mitochondrial apoptosis; silica fate remains a translational concern	[152–155]
Res@ZIF-8/TA	Colon cancer cells	Colorectal	In vitro	Tannic-acid-modified pH-responsive ZIF-8	Not reported (in vitro only)	Promoted apoptosis; inhibited migration/invasion; cell-based evidence only	[133]
99mTc-Res-AuNP	Colon cancer tissue uptake/retention	Colorectal	Biodistribution/ theranostic	Radiolabeled RES-loaded gold NPs	Physiological uptake/retention evaluated	Theranostic/biodistribution evidence rather than cytotoxic benchmark	[156]
Zein/casein/pea protein RES carriers	Caco-2/oral bioaccessibility models	Colorectal	In vitro + PK evidence	Food-grade protein matrices	Improved bioaccessibility and oral bioavailability evidence	Oral handling, bioaccessibility, stability, and chemoprevention-oriented delivery	[157–159]
Oxaliplatin + RES N,O-carboxymethyl chitosan NPs	CRC models	Colorectal	In vitro + in vivo	Chitosan co-delivery NPs	In vivo efficacy; quantitative PK not detailed	Stronger anticancer activity than free-drug or single-nanoparticle treatments	[160]
α-Mangostin + RES thiolated chitosan NPs	Colon cancer cells	Colorectal	In vitro	Mucoadhesive thiolated chitosan; dual phytochemical payload	Oral colon-oriented retention concept	Synergistic activity and mucoadhesive/pH-sensitive delivery	[161]
nChiNico-RES	HT-29	Colorectal	In vitro	Nicotinic-acid-modified chitosan NPs	Not reported (in vitro only)	Reduced HT-29 viability more effectively than free RES and unmodified RES-chitosan NPs	[162]
RES chitosan-TPP NPs	RES delivery platform/ cancer cells	Colorectal-supportive	In vitro	Ionically cross-linked chitosan-TPP	Not reported (in vitro only)	Platform-level RES encapsulation and biological activity	[163]
RES sericin NPs	Caco-2	Colorectal	In vitro	Silk-protein nanocarrier	Sustained in vitro release; no systemic PK	Selective Caco-2 inhibition; low normal-fibroblast toxicity	[164]
RES lipid-core nanocapsules	HT-29-type colon cancer cells	Colorectal	In vitro	Lipid-core nanocapsule	Not reported (in vitro only)	Improved biological activity of RES in colon-cancer cells	[165]
Curcumin/RES co-loaded biogenic silica	HCT-116, Caco-2	Colorectal	In vitro	Inorganic high-surface-area biogenic silica	Not reported (in vitro only)	Combination phytotherapy platform	[166]
β-CD nanosponges	CRC cells	Colorectal	In vitro	~185 nm; PDI <0.2; ~50× solubility	Sustained in vitro release	Photo/oxidative protection; G2/M arrest, apoptosis, Wnt/β-catenin-associated rationale	[167–172]
Biomimetic RES nano-delivery for ferroptosis	CRC models	Colorectal	Preclinical	Biomimetic nanodelivery architecture	Biodistribution/safety still require validation	Amplified ferroptosis-associated anticancer activity	[173]
PEGylated RES/DOX liposomes	MCF-7/ADR; tumor-bearing mice	Breast (MDR)	In vitro + in vivo	~130 nm; PDI <0.2; remote loading	Stable systemic circulation; intracellular DOX retention	P-gp/MDR-associated sensitization; tumor inhibition; CK-MB/LDH cardioprotection interpreted cautiously	[45,179–181]
RES/PTX co-loaded liposomes	Drug-resistant breast cancer models	Breast (MDR)	In vitro + in vivo	Co-encapsulated taxane + RES	Improved intracellular drug retention	MDR-oriented co-delivery; stronger in vivo antitumor activity	[178]
Peptide-sucrose RES liposomes (PSL@RES)	MCF-7; mouse model	Breast	In vitro + in vivo	Peptide/sucrose liposome; IC50 20.89 μM	5 mg/kg PSL@RES exceeded 10 mg/kg free RES	p53/Bcl-2/Bax/caspase-3 modulation; strong RES liposome monotherapy evidence	[182]
HA-CS-coated RES liposomes	Breast cancer cells/ CD44 targeting	Breast	In vitro	Sequential chitosan + HA/chitosan coating	Not reported (in vitro only)	CD44-associated active-targeting concept	[183]
RES-loaded SLNs	MDA-MB-231	Breast (TNBC-like)	In vitro	Solid lipid matrix	Not reported (in vitro only)	Enhanced proliferation inhibition, apoptosis, G0/G1 arrest, migration/invasion suppression; Bax/Bcl-2 increased, cyclin D1/c-Myc decreased	[184]
Microneedle-assisted RES-NLCs	MDA-MB-231; preclinical PK	Breast	In vitro + PK	NLCs delivered by microneedle arrays	Higher exposure and breast-tissue localization vs oral free RES	Localized breast delivery; enhanced internalization, cytotoxicity, and migration inhibition	[185]
Albumin-stabilized PTX/RES NPs	Breast cancer cells; tumor-bearing mice	Breast	In vitro + in vivo	Albumin-stabilized co-delivery NPs	In vivo tumor inhibition; quantitative PK not detailed	G0/G1 arrest and caspase-3/9 apoptosis; co-delivery tumor inhibition	[70,186]
Layer-by-layer tamoxifen/RES NPs	Potential TNBC/aggressive breast cancer models	Breast	In vitro	Multilayer dual-drug polymeric NPs	Not reported (in vitro only)	Early combination nanotherapy platform with endocrine-modulating agent + RES	[176]
Chitosan/RES polymeric nanocomplex	MDA-MB-231	Breast (TNBC-like)	In vitro	Chitosan-based RES complex	Not reported (in vitro only)	Autophagy-related growth inhibition; Beclin-1/ATG5/ATG7/LC3A/P62 modulation	[177,187]
PCL-based RES polymeric NPs ± TPGS	4T1; tumor-bearing mice	Breast	In vitro + in vivo	PCL NPs with/without TPGS	In vivo tumor-bearing evaluation	PCL NP without TPGS showed stronger activity; TPGS system showed possible hepatotoxicity signal	[188]
HA-conjugated polymeric micelles	MDA-MB-231; orthotopic breast models	Breast (TNBC/BCSCs)	In vitro + in vivo	~65 nm; ZP −18.5 mV; HA shell	Reduced clearance and tumor accumulation/penetration in vivo	CD44-associated uptake; EMT-marker modulation; primary tumor and lung-metastasis reduction	[189–194]
pH-responsive RES/melatonin sericin nanocarriers	MCF-7	Breast	In vitro	pH-responsive sericin network	Not reported (in vitro only)	Enhanced antiproliferative activity under acidic conditions; mechanism attributed to release/exposure rather than proven endosomal escape	[196]
RES-capped/ peptide-gated AuNP systems	MDA-MB-231; breast cancer cell models	Breast / TNBC	In vitro	~20 nm AuNPs; SPR/NIR; peptide gatekeepers in TNBC design	Not reported (in vitro only)	Chemo-photothermal synergy and targeted off-release control; metal-assisted effects require caution	[198–201]
RES-MSNs/ peptide-transferrin MSN-RES	MCF-7; in vivo tumor model for Gu et al	Breast	In vitro + in vivo	Receptor-targeted MSNs	In vivo tumor suppression in selected study; quantitative PK not reported	Proliferation/migration/invasion decreased; apoptosis induction	[202,203]
RES-loaded silver NPs	MCF-7, MDA-MB-231	Breast	In vitro	AgNP metal-payload platform	Not reported (in vitro only)	Altered viability, apoptosis, necrosis, and cell-cycle distribution; carrier-derived effects possible	[204]
RES halloysite clay nanotubes	Cancer cells	Breast-supportive	In vitro	Mineral tubular scaffold	Sustained in vitro release	Sustained release and cellular RES delivery from non-polymeric scaffold	[205]
RES-loaded HSA/albumin NPs	Breast-directed rationale; albumin NP evidence	Breast	Preclinical	~135 nm; ZP ~−25 mV; EE >88% (reported in albumin NP literature)	Prolonged circulation/tumor exposure in preclinical models	Clinically familiar carrier; gp60/SPARC relevance plausible but requires direct validation for RES-HSA breast models	[206–208]
Casein micelles + phytosomal bilayer	Breast cancer models	Breast	In vitro	Casein micellar multireservoir; monascus pigments + RES	Not reported (in vitro only)	Protein-based combination phytotherapy carrier	[209]
Shell-crosslinked zein nanocapsules	Breast cancer therapy models	Breast	Preclinical	Oral zein nanocapsules; exemestane + RES	Oral co-delivery focus; quantitative PK not in table source	Protein-based oral combination platform for endocrine therapy-associated delivery	[210]
RES-chitosan NPs + γ-irradiation	DMBA-induced breast cancer mice	Breast	In vivo	Chitosan RES nanoparticles	In vivo radiosensitizing evaluation	Reduced tumor burden; oxidative-stress, immune, p53/survivin/STAT3 markers modulated	[211]
Milk-derived exosomes (EXO-RSV / FA-Exo-RES)	MCF-7, MDA-MB-231, PTX-resistant MCF-7; mice	Breast / MDR	In vitro + in vivo	~exosome-sized biomimetic vesicles	Delivered free RES to mammary tissue; tumor-bearing survival evidence	Improved intracellular availability; nanomolar antiproliferation; spares MCF-10A; tumor burden and survival improved	[212–214]
Redox-responsive disulfide RES nanocarrier	MDA-MB-231	Breast (TNBC-like)	In vitro	GSH-responsive disulfide-containing carrier	Not reported (in vitro only)	In vitro support for redox-triggered RES release and anticancer activity	[215]
Zein/sodium hyaluronate RES NPs	Breast cancer cells	Breast	In vitro	Food-grade protein/polysaccharide carrier	Not reported (in vitro only)	Antioxidant and antitumor activity; early preclinical evidence	[216]

RES Nanoformulations in Less-Studied Malignancies

Gastric Cancer

According to GLOBOCAN 2022, stomach cancer ranked fifth for both incidence and cancer-related mortality worldwide, with approximately 969,000 new cases and 660,000 deaths in 2022.¹ Gastric cancer provides an emerging setting for RES-containing co-delivery strategies, particularly platforms designed to combine phytochemical delivery with nucleic-acid-based modulation of tumor-associated signaling.

In a representative study, Hu et al⁷⁷ fabricated polysaccharide-based mesoporous silica nanoparticles co-loaded with anti-miR21 and resveratrol, with surface conjugation of hyaluronic acid (HA) to direct active targeting toward CD44-overexpressing gastric carcinoma cells (HA/RSVmirNP). Polyethylenimine (PEI) modification of the MSN surface served as a cationic anchoring layer for stable anti-miR21 immobilization, while the mesoporous matrix accommodated RES within its hydrophobic interior. Confocal laser-scanning microscopy and flow cytometry confirmed significantly elevated cellular internalization of HA/RSVmirNP relative to non-targeted RSVmirNP, and in vitro apoptosis assays demonstrated synergistic cytotoxicity arising from concurrent miR-21 silencing and RES-induced mitochondrial apoptosis. Critically, in BGC-823 xenograft-bearing mice, HA/RSVmirNP achieved approximately threefold greater tumor regression than free RES and twofold greater regression than the non-targeted nanoformulation, while maintaining favorable systemic safety profiles.⁷⁷

This study illustrates two design principles of broader significance for RES nanomedicine: (i) co-delivery of a hydrophobic polyphenol payload with a nucleic-acid therapeutic can be achieved using hybrid MSN architectures that combine mesoporous drug-loading domains with cationic nucleic-acid-binding components; and (ii) ligand-mediated active targeting, exemplified by HA–CD44 recognition, can improve cellular internalization and antitumor activity compared with non-targeted counterparts in CD44-overexpressing gastric cancer models.⁷⁷ In a related gastric cancer study, a RES-loaded MSN/PEI-FA platform was constructed, confirming the feasibility of PEI-FA functionalization for RES-MSN delivery, although this system did not evaluate nucleic-acid co-delivery.²¹⁷ Therefore, direct extension of RES–nucleic-acid MSN platforms to phenotypically heterogeneous or peritoneally disseminated malignancies remains a rational future direction rather than an experimentally demonstrated outcome.

Glioma and Glioblastoma

Brain tumors provide another relevant but still preclinical application domain for RES nanocarriers. Lipid-core nanocapsules loaded with RES reduced glioma growth in both in vitro and in vivo models.²¹⁸ Transferrin-targeted PEGylated RES liposomes (Tf-RES-L) further extended this strategy to glioblastoma by exploiting transferrin receptor overexpression at the blood-brain barrier and on GBM cells, improving tumor-cell uptake and prolonging median survival in glioma xenograft models.²¹⁹ Subsequent evaluation in glioblastoma neurosphere cultures further supported activity against tumor-initiating-cell-like populations that are relevant to recurrence and treatment resistance.²²⁰ These studies provide comparatively mature preclinical support for brain-directed RES nanocarrier design because they combine disease-relevant in vivo evaluation with receptor-mediated delivery strategies intended to improve access to glioma tissue. Nevertheless, clinical validation of RES nanocarriers in glioma or glioblastoma remains unavailable.

Hepatocellular Carcinoma and Liver-Targeted Platforms

RES-loaded chitosan-TPP nanoparticles preserved antiproliferative activity against SMMC-7721 hepatocellular carcinoma cells while exhibiting lower cytotoxicity toward normal L02 hepatocytes, supporting selective in vitro cytotoxicity rather than demonstrated liver-targeted delivery.^163,221 Inorganic theranostic approaches have also been explored, with Res-GNPs enhancing anti-hepatoma effects in HepG2 cells and xenograft models through stronger proliferation inhibition and apoptosis induction (downregulation of pro-caspase-9/3, PI3K, Akt; upregulation of caspase-8, Bax) and significant tumor growth suppression with reduced VEGF expression.²²² In the reported xenograft experiment, histopathological examination did not reveal obvious treatment-associated injury in the examined major organs under the tested conditions. Collectively, these studies support liver-directed RES nanocarrier development, with Res-GNPs providing direct in vivo antitumor evidence and chitosan-based systems contributing complementary biodegradable delivery strategies. However, inorganic gold-based platforms and biodegradable polysaccharide carriers should be evaluated separately with respect to biodistribution, long-term retention, and carrier-specific safety.

Skin Cancer and Melanoma

Cutaneous malignancies represent a logical extension of local RES nano-delivery because topical or intradermal routes can bypass systemic bioavailability barriers. Ultradeformable liposomes co-loading RES and 5-fluorouracil were developed for topical delivery in non-melanoma skin cancer models,²²³ while RES-loaded nanocapsules inhibited murine melanoma tumor growth.²²⁴ A more recent invasome gel formulation further supports topical RES nanocarrier development for skin cancer, with RSV-loaded invasomes (208.7 ± 74 nm, EE 77.7%, ZP −70.4 mV) achieving IC₅₀ = 6.34 μg/mL in squamous carcinoma cells and significant tumor volume reduction in Ehrlich-induced mice models via BAX/Caspase-3 upregulation and NF-κB/BCL-2 downregulation.²²⁵ These studies illustrate route-specific design principles that differ from systemic EPR-dependent delivery. Importantly, the melanoma-specific in vivo evidence is provided primarily by RES-loaded nanocapsules, whereas the invasome-gel study should be interpreted as supporting topical local-delivery feasibility and local antitumor activity rather than as definitive validation in melanoma.

Ovarian Cancer

Ovarian cancer represents an emerging indication for RES nanoformulations in which the available evidence extends beyond cell-based proof of concept. Weżgowiec et al²²⁶ evaluated resveratrol-loaded and curcumin-loaded core–shell nanocarriers in MDAH-2774 and cisplatin-resistant SKOV-3 ovarian cancer cell lines. RES-loaded formulations produced formulation- and cell-line-dependent cytotoxic effects, with MDAH-2774 cells generally showing greater sensitivity than SKOV-3 cells, supporting the feasibility of nanocarrier-mediated RES delivery in both sensitive and drug-resistant ovarian cancer cell models. Because this study was limited to in vitro evaluation, it provides cellular-level evidence only; in vivo biodistribution and efficacy remain untested.

Combination polymeric micelles provide a complementary ovarian-cancer-relevant strategy in which RES functions primarily as a co-delivered chemosensitizing and toxicity-modulating payload rather than as a stand-alone anticancer agent. Al Fatease et al²²⁷ developed combinational polymeric micelles for the co-delivery of quercetin/resveratrol or resveratrol/curcumin with doxorubicin in ovarian cancer and reported enhanced chemosensitization together with mitigation of doxorubicin-associated cardiotoxicity. This work therefore supports the incorporation of RES into combination nanocarriers intended to improve chemotherapy response and tolerability in ovarian cancer, rather than establishing the efficacy of RES nano-monotherapy.

Albumin-based nanoparticles further strengthen the ovarian-cancer evidence base. Guo et al²²⁸ reported that RES-loaded bovine serum albumin nanoparticles induced cell death in human ovarian cancer cells through caspase-dependent and caspase-independent pathways, providing mechanistic in vitro support for albumin-mediated RES delivery. More importantly, Long et al²²⁹ developed RGD-conjugated RES-loaded human serum albumin nanoparticles and evaluated their pharmacokinetic behavior and tissue distribution in the context of ovarian cancer therapy. These findings indicate that ovarian-cancer-directed RES nanodelivery has progressed beyond cell-based evaluation to include in vivo delivery assessment.

Taken together, the available studies position ovarian cancer as an indication with limited but direct in vivo RES nanocarrier evidence. Core–shell systems provide recent cellular evidence in sensitive and cisplatin-resistant ovarian cancer models, combination micelles support the use of RES as an adjunctive co-payload with doxorubicin, and RGD-functionalized albumin nanoparticles provide the most translationally relevant delivery evidence reported to date. Nevertheless, further evaluation in disseminated, ascites-bearing, or orthotopic ovarian cancer models is required before route-specific delivery strategies or clinical prioritization can be defined with confidence.

Oral Squamous Cell Carcinoma

Oral squamous cell carcinoma (OSCC) is characterized by a highly immunosuppressive TME enriched in tumor-associated macrophages and cancer-associated fibroblasts, which collectively promote treatment resistance and local invasion. Two distinct nanoformulation strategies have been evaluated for this indication, each at a different evidence maturity level.

Tao et al²³⁰ designed dandelion-like size-shrinkable nanoparticles (RC-GMN) co-encapsulating resveratrol and chlorin e6 (Ce6), modified with the EGFR-targeting ligand GE11 and a hyaluronic-acid nanogel shell, for targeted photodynamic therapy of orthotopic oral squamous cell carcinoma in mice. Resveratrol mitigated tumor hypoxia by inhibiting cellular oxygen consumption, thereby enhancing Ce6-mediated reactive oxygen species generation and inducing combined autophagic cell death and apoptosis. Mohan et al²³¹ coencapsulated RES and 5-fluorouracil in PEGylated nanoliposomes and evaluated the formulation against head and neck squamous cell carcinoma, providing direct in vitro evidence for dual-drug liposomal RES delivery in this anatomical setting. More recently, topical chitosan nanoparticles carrying RES were evaluated in chemically induced epithelial dysplasia of the hamster buccal pouch, extending the local-delivery concept toward an animal model of premalignant oral mucosal disease.²³²

Accordingly, the most advanced malignant OSCC evidence supports RES primarily as a hypoxia-modulating co-payload within nanocarrier-enabled photodynamic therapy rather than as a validated nanoformulated monotherapy. In parallel, the topical chitosan nanoparticle study supports local intervention in premalignant oral mucosal disease, but should not be interpreted as direct therapeutic evidence in established invasive OSCC.

Cervical Cancer

Cervical cancer represents an intermediate evidence tier for RES formulation strategies. The strongest formulation-specific in vivo evidence is derived from a hydroxypropyl-β-cyclodextrin-complexed RES formulation rather than from an advanced multifunctional nanoparticle platform. Hao et al²³³ demonstrated that hydroxypropyl-β-cyclodextrin-complexed RES (RHSD) suppressed tumor growth more effectively than free RES in a HeLa xenograft model and was associated with reduced HPV E6/E7 expression together with restored p53 and Rb1 protein expression. Importantly, RHSD is an inclusion-complex formulation; therefore, this study supports the capacity of formulation optimization to enhance RES activity in vivo, but should not be presented as validation of a targeted or multifunctional RES nanocarrier.

At the cell-study level, Tomoaia et al²³⁴ evaluated the effects of resveratrol in combination with doxorubicin-mediated gold nanoparticle treatment in HeLa and CaSki cervical cancer cells. Overall, engineered RES-containing nanocarrier evidence in cervical cancer remains limited, and further disease-specific in vivo evaluation is required.

Pancreatic Cancer

Pancreatic ductal adenocarcinoma presents a major delivery challenge because of its dense desmoplastic stroma, which contains activated pancreatic stellate cells, abundant hyaluronic acid, and a collagen-rich extracellular matrix. This fibrotic barrier limits drug penetration and vascular perfusion, contributing to the poor response of pancreatic cancer to conventional chemotherapy.

Gold nanoparticle-RES complexes (mean diameter: ≈30 nm; PVP-stabilized; SPR peak at 530 nm) were evaluated in KRAS-mutant AsPC-1 and KRAS-wild-type BxPC-3 pancreatic cancer cell lines.^235,236 The selection of AuNPs for this indication is strategically significant: their ultra-small size of around 30 nm facilitates diffusion through the restrictive stromal architecture, while PVP surface stabilization prevents aggregation within the dense extracellular matrix. The AuNP-RES complex specifically targeted KRAS-mutant cells, inducing G0/G1 cell cycle arrest and enhanced apoptosis with an IC₅₀ of 20.5 µM versus 52.1 µM for free RES in AsPC-1 cells—a 2.5-fold improvement. Furthermore, the photothermal-conversion capacity of AuNPs may provide an adjunctive strategy for transient stromal modulation through localized hyperthermia, potentially enhancing subsequent drug penetration. However, current evidence is derived from monolayer cell cultures, which do not recapitulate the dense stromal barrier that defines pancreatic cancer in vivo. Validation in orthotopic pancreatic cancer models with established desmoplasia is therefore needed.

In addition to gold-based systems, lipid-vesicular magnetic platforms have recently been investigated for pancreatic cancer. Firouzi Amandi et al²³⁷ fabricated a magnetic niosomal platform for RES delivery and evaluated its anticancer activity against human pancreatic Capan-1 cells. This study adds a distinct design option to the pancreatic RES nanomedicine landscape by combining vesicular encapsulation with magnetic responsiveness. However, because the current evidence remains cell-based, orthotopic pancreatic cancer models with established desmoplasia are still required before its translational relevance can be assessed.

Translational Summary and Prioritization

These pancreatic-cancer studies exemplify the broader pattern across less-studied malignancies: RES nanocarrier evidence is increasingly diverse, but disease-specific validation often remains one or two experimental steps behind the most advanced prostate, lung, colorectal, and breast cancer platforms. The evidence supporting RES-containing delivery systems in malignancies beyond prostate, lung, colorectal, and breast cancers is heterogeneous and should be interpreted according to the most advanced disease-specific model available rather than the number of formulation reports alone. Direct in vivo antitumor evidence for RES-containing delivery systems has been reported in gastric cancer, glioma/glioblastoma, hepatocellular carcinoma, ovarian cancer, melanoma, and orthotopic oral squamous cell carcinoma combination-photodynamic models. Topical cutaneous delivery systems have also shown local antitumor feasibility, although not all available animal models are histology-specific for skin cancer. Importantly, the therapeutic role of RES differs across these settings: in oral squamous cell carcinoma, the most advanced evidence supports RES primarily as a hypoxia-modulating co-payload within photodynamic nanotherapy, whereas in gastric cancer, glioma, hepatocellular carcinoma, melanoma, and ovarian cancer, RES-containing carriers have been evaluated more directly for tumor-directed delivery or antitumor activity.

Cervical cancer currently represents a formulation-responsive but underdeveloped indication. The HP-β-cyclodextrin/RES inclusion complex has demonstrated improved antitumor activity relative to free RES in a cervical cancer xenograft model, supporting the value of formulation-enhanced RES delivery in this disease setting. However, this evidence should be distinguished from validation of advanced engineered RES nanoparticles, because disease-specific nanoparticle studies remain limited. Future prioritization should therefore place cervical cancer behind indications with stronger disease-specific in vivo nanocarrier evidence, while still recognizing it as a relevant model for testing formulation-enhanced RES activity.

Across all of these additional malignancies, the available studies remain preclinical and do not yet establish anticancer efficacy of RES nanocarriers in patients. This evidence hierarchy supports a cautious translational strategy centered on reproducible manufacturing, route-relevant pharmacokinetics, carrier-specific safety assessment, and carefully justified early-phase evaluation. Representative RES-loaded nanoformulations evaluated across these additional cancer indications are summarized in Table 4.

Table 4.

Summary of Representative RES-Loaded Nanoformulations Evaluated in Other Cancer Indications

Nanoformulation	Model/Cell Line	Cancer (Subtype)	Evidence	Key Physicochemical/ Design Features	PK/Biodistribution	Outcomes and Mechanisms	Ref.
HA/RSVmirNP (HA/Res-anti-miR21-MSN)	BGC-823 xenograft; CD44-overexpressing gastric cells	Gastric	In vitro + in vivo	MSN/PEI with HA targeting and anti-miR21 + RES co-loading	In vivo regression; systemic safety favorable in reported model	miR-21 silencing + RES mitochondrial apoptosis; ~3× greater regression than free RES, ~2× than non-targeted formulation	[77]
RES-MSN/PEI-FA	Gastric carcinoma cells	Gastric	In vitro	PEI-FA-functionalized MSN	Not reported (in vitro only)	Feasibility of PEI-FA functionalization for RES-MSN delivery	[217]
RES lipid-core nanocapsules	Glioma in vitro + in vivo models	Glioma	In vitro + in vivo	Lipid-core nanocapsule	In vivo activity; quantitative PK not reported	Reduced glioma growth	[218]
Transferrin-targeted PEG liposomes (Tf-RES-L)	Glioma xenograft; GBM neurospheres	Glioma / GBM	In vitro + in vivo	PEG liposome with transferrin ligand	TfR-mediated BBB/tumor uptake; in vivo survival outcome	Improved tumor uptake; prolonged median survival; activity in tumor-initiating neurospheres	[219,220]
RES-loaded chitosan-TPP NPs	SMMC-7721; normal L02	Hepatocellular carcinoma	In vitro	Ionic-crosslinked chitosan-TPP	Not reported (in vitro only)	Preserved antiproliferative activity with lower L02 cytotoxicity; selective in vitro cytotoxicity rather than proven liver targeting	[163,221]
RES-gold NPs (Res-GNPs)	HepG2; xenograft mice	Hepatocellular carcinoma	In vitro + in vivo	Gold-RES conjugate	Tumor suppression; no obvious vital-organ injury in tested conditions	Caspase-8/Bax increased; pro-caspase-9/3, PI3K/Akt and VEGF decreased; tumor growth suppressed	[222]
Ultradeformable liposomes (RES + 5-FU)	Non-melanoma skin cancer models	Skin/NMSC	In vitro/topical	Ultradeformable topical liposomes	Topical delivery; systemic PK not reported	Topical multidrug delivery feasibility	[223]
RES-loaded nanocapsules	Murine melanoma	Skin/melanoma	In vivo	Polymeric nanocapsules; local/topical strategy	Local in vivo delivery; systemic PK not reported	Inhibited murine melanoma tumor growth	[224]
RSV-loaded invasome gel	Squamous carcinoma cells; Ehrlich-induced mice	Skin/SCC-oriented	In vitro + in vivo	208.7 ± 74 nm; EE 77.7%; ZP −70.4 mV	Topical in vivo activity; systemic PK not reported	IC50 6.34 μg/mL; tumor volume decreased; BAX/Caspase-3 increased; NF-κB/BCL-2 decreased	[225]
Core-shell NPs (RES or curcumin)	MDAH-2774, cisplatin-resistant SKOV-3	Ovarian	In vitro	~150 nm core–shell nanocarriers	No in vivo PK/biodistribution	Formulation- and cell-line-dependent cytotoxicity; MDAH-2774 generally more sensitive than SKOV-3	[226]
Combination polymeric micelles (quercetin/RES or RES/curcumin + DOX)	Ovarian cancer models	Ovarian	In vitro / preclinical	Micellar co-delivery	Not reported in table source	Chemosensitization and mitigation of DOX-associated cardiotoxicity; RES as adjunctive co-payload	[227]
RES-BSA NPs	Human ovarian cancer cells	Ovarian	In vitro	Bovine serum albumin NPs	Not reported (in vitro only)	Caspase-dependent and caspase-independent cell death	[228]
RGD-conjugated RES-HSA NPs	Ovarian cancer therapy model	Ovarian	In vitro + in vivo delivery	RGD-targeted albumin nanoparticles	PK and tissue distribution evaluated	Most delivery-relevant ovarian evidence; targeted albumin platform	[229]
Size-shrinkable RES/Ce6 NPs (RC-GMN; GE11/HA nanogel)	Orthotopic OSCC mice	Oral squamous cell carcinoma	In vitro + in vivo	Dandelion-like; GE11 EGFR ligand; HA nanogel shell	Orthotopic PDT activity; quantitative PK not detailed	RES mitigated tumor hypoxia and enhanced Ce6 ROS; autophagic death + apoptosis	[230]
PEGylated nanoliposomes (RES + 5-FU)	Head and neck SCC	HNSCC / oral region	In vitro	PEGylated dual-drug liposomes	Not reported (in vitro only)	Direct in vitro evidence for RES/5-FU liposomal co-delivery	[231]
Topical RES-loaded chitosan NPs	Hamster buccal-pouch epithelial dysplasia	Oral premalignant mucosa	In vivo	Topical chitosan nanoparticles	Local delivery; systemic PK not reported	Local intervention in chemically induced epithelial dysplasia; not direct invasive OSCC efficacy	[232]
HP-β-CD/RES inclusion complex (RHSD)	HeLa xenograft mice	Cervical	In vitro + in vivo	Cyclodextrin inclusion complex; not a targeted multifunctional NP	In vivo tumor suppression vs free RES	HPV E6/E7 decreased; p53/Rb1 restored; formulation-enhanced RES activity	[233]
Doxorubicin + RES + AuNP-associated treatment	HeLa, CaSki	Cervical (HPV+)	In vitro	Gold nanoparticle-associated doxorubicin + RES combination	Not reported (in vitro only)	Feasibility of RES combined with gold-nanoparticle-associated chemotherapy; not in vivo RES nanocarrier validation	[234]
AuNP-RES complex (PVP-stabilized)	AsPC-1 KRAS-mutant, BxPC-3 KRAS-WT	Pancreatic	In vitro	~30 nm; PVP-stabilized; SPR 530 nm	Not reported (monolayer in vitro only)	KRAS-mutant cell selectivity; G0/G1 arrest; IC50 20.5 vs 52.1 μM for free RES	[235,236]
Magnetic niosomal RES platform	Capan-1	Pancreatic	In vitro	Vesicular magnetic-responsive platform	Not reported (cell-based only)	Anticancer activity against pancreatic cells; orthotopic/desmoplastic validation needed	[237]

Clinical Translation of Resveratrol Nanoformulations: Current Progress and Translational Barriers

The clinical translation of RES nanoformulations can be assessed through two linked questions: what human evidence currently exists, and why advanced engineered RES nanocarriers remain largely absent from oncology trials despite extensive preclinical activity. Current clinical studies are still dominated by conventional RES, micronized formulations, dietary phytochemical sources, or first-generation formulation enhancements, whereas engineered nanocarriers have only limited oncology-associated clinical entry. The major translational barriers include inconsistent translation of preclinical efficacy into human outcomes, patient-to-patient variability in nanoparticle tumor delivery, difficulties in manufacturing and scale-up, unresolved carrier-specific safety concerns, and the modest intrinsic clinical potency of RES. These barriers are mutually reinforcing and define the research priorities for future RES nanomedicine development.

Current Clinical Progress

As of early 2026, oncology-related clinical evaluations of RES remain dominated by unformulated purified RES, micronized suspensions, dietary phytochemical sources, and first-generation formulation enhancements such as phospholipid complexes or lozenges. The clearest example of formulation-enhanced clinical evaluation is SRT501 (micronized resveratrol suspension). In a Phase I pilot study of patients with colorectal cancer and hepatic metastases, daily oral administration of 5.0 g of the micronized formulation for 14 days increased systemic exposure compared with historical reports for non-micronized RES, and LC-MS/MS analysis confirmed parent RES accumulation in resected hepatic tissue, accompanied by increased cleaved caspase-3 in malignant lesions.^238,239 These findings indicate that formulation enhancement can improve RES tissue distribution and pharmacodynamic activity in oncology patients.

However, improved exposure does not automatically translate into acceptable safety. A randomized phase II trial of the same micronized RES formulation combined with bortezomib in relapsed or refractory multiple myeloma was terminated prematurely because of cast nephropathy and renal failure.²⁴⁰ The cause of this renal toxicity remains uncertain, but the trial highlights the need for careful toxicity profiling when formulation strategies increase RES exposure.²⁴¹

To contextualize the translational status of RES beyond the micronized resveratrol program, a comprehensive survey of ClinicalTrials.gov and international trial registries (including EudraCT/CTIS, WHO ICTRP, ISRCTN, and institutional ethics-approved studies) was conducted. As of early 2026, our registry and literature search identified approximately 20 oncology-related or cancer-prevention-associated clinical evaluations involving RES, RES-containing dietary interventions, or first-generation RES formulation enhancements. These studies include completed, terminated, withdrawn, and actively recruiting trials, but most involve conventional oral RES, micronized RES, dietary phytochemical sources, or simple formulation-enhancement strategies rather than advanced engineered nanocarriers. Notably, the recent randomized open-label trial conducted at the Medical University of Warsaw (KB/24/2023) constitutes the first identified oncology-associated human study using a commercial liposomal RES formulation.¹⁰ In this study, 72 head and neck cancer patients receiving home enteral nutrition were randomized to receive either 400 mg/day of liposomal RES or standard enteral nutrition alone for 12 weeks; the liposomal RES arm demonstrated a selective and significant increase in glutathione peroxidase (GPx) activity and a beneficial elevation of bioelectrical phase angle, an emerging marker of cellular integrity. However, the simultaneous rise in malondialdehyde (MDA) levels indicates that redox-related safety signals should be monitored carefully when formulation strategies increase RES exposure. This trial represents an early clinical foothold for liposomal RES in oncology-associated supportive care, but it does not establish anticancer efficacy of engineered RES nanocarriers.

Among the completed studies, several Phase I trials have established the foundational pharmacokinetic and safety profile of RES in oncology. A Phase I trial (NCT00098969) evaluated single escalating doses ranging from 0.5 to 5.0 g in healthy volunteers, demonstrating dose-proportional increases in plasma RES and metabolite concentrations with mild GI side effects at the highest dose.^242,243 Two independent Phase I studies in resectable colorectal cancer patients (NCT00256334 and NCT00433576) confirmed that orally administered RES reaches colonic mucosal tissue in quantifiable parent compound concentrations, with NCT00256334 reporting a 5% decrease in Ki-67 proliferation marker expression following 8 days of treatment at 0.5–1.0 g/day.²⁴⁴ For breast cancer chemoprevention, a Phase I trial (NCT01370889) involving high-risk postmenopausal women demonstrated that a low-dose RES regimen—administered at 5 to 50 mg twice daily for 12 weeks—decreased the methylation of the tumor suppressor gene RASSF-1α, providing a potential epigenetic mechanism for chemoprevention.²⁴⁵ In biochemically recurrent prostate cancer, muscadine grape skin extract (MPX) containing RES was evaluated in a Phase I/II study, yielding a non-significant 5.3-month prolongation of PSA doubling time at the higher dose (4000 mg/day),^246,247 insufficient to support therapeutic recommendation. Furthermore, to understand its localized pharmacokinetics in solid organs, a Phase I/II interventional study (NCT02261844) was originally designed to evaluate the hepatic-tissue distribution and hepatocyte-function effects of orally administered RES (1 g/day × 10 days pre-resection) in patients undergoing elective liver surgery for hepatocellular carcinoma, but was ultimately withdrawn prior to enrollment due to loss of funding (per registry update).

Beyond the trials discussed above, several additional conventional-formulation studies further define the landscape. A Phase 0 biological study at the University of Wisconsin (NCT01476592) administered 5 g/day of unformulated RES in two divided doses for up to three 28-day cycles to patients with low-grade gastrointestinal neuroendocrine tumors, with the primary endpoint of evaluating Notch-1 pathway activation (full-length Notch-1, cleaved Notch-1, HES-1, and ASCL-1) in pre- versus post-treatment tumor biopsy specimens, building directly upon the earlier high-throughput-screen identification of RES as the strongest endogenous Notch activator among 7,264 candidate compounds.^248,249 A separate randomized double-blind pilot trial (NCT01324089) examined whether co-administration of piperine (5 or 25 mg) with 2.5 g of RES could enhance plasma RES exposure in healthy volunteers, framed within a cancer chemoprevention context, although piperine bioenhancement does not constitute a true nanocarrier strategy.²⁵⁰ The Division of Cancer Prevention at the National Cancer Institute also conducted a Phase I trial in healthy adults (NCT00721877) characterizing safety, pharmacokinetic parameters, and biomarker responses of repeat-dose RES administration, complementing the foundational single-dose PK data from NCT00098969.²⁵¹ A radiotracer trial registered with the European Clinical Trials Database (EudraCT 2007–002131-91) administered [¹⁴C]-radiolabeled RES at either a “dietary-achievable” (5 mg) or “pharmacological” (250 mg) single oral dose to prostate cancer patients prior to surgery, employing accelerator mass spectrometry to demonstrate that prostate tissue concentrations of parent RES are markedly lower than those of its glucuronide and sulfate conjugates—providing direct human-tissue evidence that conventional oral RES at doses ≤ 1 g/day is unlikely to achieve antiproliferative concentrations in prostate, and thereby supplying a strong mechanistic rationale for nanocarrier-mediated bioavailability enhancement.²⁵² Finally, a Phase I biomarker trial of dietary grape-derived RES for colon cancer prevention (NCT00578396) was registered but ultimately withdrawn before enrollment by the sponsor,²⁵³ highlighting the inherent difficulty of designing dietary-source RES trials with consistent and verifiable dosing.

Three further trials—two multi-component dietary interventions and one pro-oxidant drug-combination study—must also be considered for a complete translational landscape, although the polypharmacy of the dietary studies precludes attribution of any observed effect specifically to RES. First, a Phase II single-arm dietary intervention trial in stage III/IV follicular lymphoma patients (NCT00455416, KLYMF, Oslo University Hospital) administered Merlot grape juice—a dietary source of RES and quercetin—alongside omega-3 fatty acids, selenium, garlic-derived allicin, pomegranate juice (ellagic acid), and green tea (epigallocatechin gallate) for at least six months, with primary endpoints assessing cell-proliferation and apoptosis biomarkers, host immune-cell infiltrate, and oxidative stress in lymph-node biopsies; this represents the only registered RES-containing trial in a hematologic malignancy other than the multiple myeloma study using the micronized RES formulation.²⁵⁴ Second, a Phase I/II randomized phytochemical-diet trial in localized prostate cancer (NCT00433797 / EudraCT 2006–006679-18, University of Oslo) supplemented patients with a multi-component diet comprising grape juice, tomato, pomegranate juice, green tea, soy, selenium, and polyunsaturated fatty acids for three weeks before prostatectomy, evaluating effects on serum PSA kinetics and tissue oxidative-stress biomarkers.²⁵⁵ Third, and most directly relevant to the central thesis of this review, an exploratory window-of-opportunity trial conducted at the Tata Memorial Centre in India (CTRI/2018/03/012459, RESCU 004) administered an oral pro-oxidant combination of RES and chelated copper (R-Cu) twice daily for two weeks to 20 patients with advanced oral squamous cell carcinoma (OSCC), with five additional patients serving as untreated controls. Pilankar et al²⁵⁶ reported marked R-Cu-mediated deactivation of cell-free chromatin particles in the tumor microenvironment, accompanied by significant downregulation of 21 of 23 hallmark-of-cancer biomarkers and five immune checkpoints; intriguingly, the lowest dose tier (5.6 mg RES paired with 560 ng Cu) was more effective than the highest tier (500 mg RES paired with 5 mg Cu), and no R-Cu-attributable adverse events were observed. This inverse dose-response provides supportive human-tissue evidence for a non-linear RES pharmacodynamic response and represents a cautionary signal for RES nanomedicine development, in which carrier-mediated intracellular dose escalation may push tumor exposure beyond the intended therapeutic window.

A recent pilot study in glioblastoma multiforme (GBM) patients represents a related low-dose RES–copper strategy. Ten patients awaiting surgery received a bi-layered tablet combining ultra-low-dose RES (5.6 mg) with copper (560 ng) four times daily for a mean of 11.6 days.²⁵⁷ The pro-oxidant combination was designed to generate ROS that deactivate cell-free chromatin particles released from dying tumor cells. Analysis of resected tissue demonstrated marked deactivation of chromatin particles in the tumor microenvironment and downregulation of oncogenic markers compared with untreated controls. While preliminary and not a nanocarrier study, this trial supports the need to consider non-linear dose-response behavior when designing RES formulations that increase intracellular exposure.

The most significant ongoing clinical initiative is the COLO-PREVENT trial (ISRCTN13526628),²⁵⁸ a Cancer Research UK-funded Phase II/III platform trial conducted within the English and Welsh NHS Bowel Cancer Screening Programme. This multi-center study, which is planned across 60 sites, includes a resveratrol sub-trial that will randomize 477 participants with high-risk colorectal polyps. Patients will receive purified RES at doses of 5 mg/day, 1 g/day, or a placebo for a duration of 12 months, with polyp recurrence at surveillance colonoscopy as the primary endpoint. COLO-PREVENT represents the largest and most rigorous clinical evaluation of RES in cancer prevention to date and, if positive, could provide the definitive evidence needed to establish RES as a standard chemopreventive agent for colorectal polyp management. Notably, the inclusion of both a low dose (5 mg) and a high dose (1 g) arm will generate critical dose-response data relevant to the therapeutic window considerations.

Two first-generation formulation enhancement approaches have also undergone clinical evaluation, though neither constitutes a true nanodelivery system. Transmucosal delivery via RES lozenges demonstrated enhanced systemic exposure compared to conventional GI absorption in healthy volunteers by bypassing hepatic first-pass metabolism, though validation in cancer cohorts is lacking.²⁵⁹ RES-phospholipid complexes achieved a 29-fold increase in plasma RES AUC relative to standard extracts, yet their oncological utility remains exploratory.^112,260 While these formulation strategies represent incremental improvements over unformulated RES, they address only the bioavailability limitation without providing the tumor targeting, controlled release, or co-delivery capabilities that define the advanced nanocarrier platforms. The clinical landscape shown in Table 5 therefore reveals three main gaps: advanced engineered RES nanocarriers have not yet been clinically validated for anticancer efficacy; clinical evidence remains concentrated mainly in colorectal chemoprevention and formulation-enhanced exposure; and nanoformulation-optimized dose, route, and biomarker selection remain underexplored. These observations support prioritizing clinically familiar and manufacturable platforms, particularly PLGA- and lipid-based systems, for early pharmacokinetic, safety, and biomarker-guided studies.²⁶¹

Table 5.

Clinical and Adjacent Early-Stage Evaluations of RES Formulations Relevant to Cancer Translation

Registry No.	Formulation	Phase/Stage	Indication/Population	Dose and Duration	Status	Key findings/Toxicity
NCT00920803	Micronized RES (SRT501)	Phase I	CRC with hepatic metastases	5.0 g/day oral; 14 d pre-surgery	Completed	Plasma exposure > non-micronized reports; hepatic parent RES detected; cleaved caspase-3 increased in malignant lesions.
NCT00920556	Micronized RES + bortezomib	Phase II	Relapsed/refractory multiple myeloma	5.0 g/day + bortezomib	Terminated	Stopped early for unexpected cast nephropathy/renal failure; toxicity etiology ambiguous.
NCT00098969	Unformulated RES	Phase I	Healthy volunteers/ chemoprevention PK	0.5–5.0 g single dose	Completed	Dose-proportional plasma RES/metabolites; mild GI effects at highest dose.
NCT00256334	Unformulated RES	Phase I	Resectable CRC	0.5–1.0 g/day; 8 d pre-surgery	Completed	Parent RES reached colonic mucosa; ~5% Ki-67 decrease reported.
NCT00433576	Unformulated RES	Phase I	Resectable CRC	Escalating oral dosing; pre-surgery	Completed	Mucosal PK evidence; parent compound quantifiable in colonic tissue.
NCT01370889	Unformulated RES	Phase I	High-risk postmenopausal women (breast)	5 or 50 mg BID; 12 wk	Completed	RASSF-1α methylation decreased; sex-steroid effects; favorable safety.
NCT01317199	Muscadine grape skin extract (MPX)	Phase I/II	Biochemically recurrent prostate cancer	500 or 4000 mg/day; 6 mo	Completed	Non-significant +5.3-month PSA doubling-time signal at high dose; insufficient for recommendation.
NCT01476592	Unformulated RES	Phase 0	Low-grade GI neuroendocrine tumors	5 g/day; up to 3 × 28-d cycles	Completed	Notch-1 pathway activation endpoint; based on RES as strongest Notch activator in high-throughput screen.
NCT01324089	RES ± piperine	Pilot RCT	Healthy volunteers / chemoprevention PK	RES 2.5 g ± piperine 5/25 mg	Completed	Piperine bioenhancement study; not a nanocarrier.
NCT00721877	Unformulated RES	Phase 0/I	Healthy adults (NCI prevention)	Repeat-dose oral	Completed	Repeat-dose PK and biomarker safety data; complements single-dose PK evidence.
EudraCT 2007–002131-91	[14C]-radiolabeled RES	Window-of-opportunity PK	Prostate cancer pre-prostatectomy	5 mg vs 250 mg single dose	Completed	Accelerator-MS showed prostate parent RES far below conjugates; rationale for delivery enhancement.
NCT00578396	Dietary grape-derived RES	Phase I biomarker	Colon cancer prevention	Fresh red grapes × 28 d	Withdrawn	Included for completeness; dietary-source dose standardization difficulty.
NCT00455416	Merlot grape juice + multi-component phytochemical diet	Phase II single-arm	Stage III/IV follicular lymphoma	At least 6 months	Completed / registry-listed	RES-containing polypharmacy; endpoints included proliferation/apoptosis biomarkers, immune infiltrate, oxidative stress; attribution to RES not possible.
NCT00433797 / EudraCT 2006–006679-18	Multi-component phytochemical diet including grape juice	Phase I/II randomized	Localized prostate cancer pre-prostatectomy	3 wk before prostatectomy	Completed / registry-listed	Dietary mixture evaluated serum PSA kinetics and tissue oxidative-stress biomarkers; not RES-specific.
CTRI/2018/03/012459 (RESCU 004)	RES + chelated copper (R-Cu)	Exploratory window-of-opportunity	Advanced oral squamous cell carcinoma	Twice daily × 2 wk; dose-tiered	Completed	Marked deactivation of cell-free chromatin particles and broad biomarker downregulation; lowest dose tier more active; no attributable AEs reported.
Not registered (pilot)	RES + copper bi-layered tablet	Pilot	Glioblastoma multiforme	5.6 mg RES + 560 ng Cu QID; mean 11.6 d	Completed	Pro-oxidant strategy deactivated cell-free chromatin particles and reduced oncogenic markers in resected tissue; not a nanocarrier.
ISRCTN13526628	Purified RES	Phase II/III	CRC polyp prevention (NHS BCSP)	5 mg or 1 g/day vs placebo; 12 mo	Recruiting	Primary endpoint polyp count; dose-response arms.
Not registered (PoC)	RES lozenge (transmucosal)	Proof of concept	Healthy volunteers/ bioavailability	Single-dose lozenge	Completed	Enhanced systemic exposure via buccal route; cancer validation lacking.
Not registered (PK)	RES-phospholipid complex	Exploratory PK	Healthy subjects	Single and repeat dosing	Completed	~29× plasma RES AUC increase vs standard extract; oncologic utility exploratory.
NCT02261844	Unformulated RES	Phase I/II	Hepatocellular carcinoma/ elective liver surgery	1 g/day × 10 d pre-resection	Withdrawn	Designed for hepatic-tissue distribution/hepatocyte-function effects; never enrolled due to funding.
KB/24/2023	Commercial liposomal RES	Randomized open-label RCT	Head & neck cancer on home enteral nutrition (n=72)	400 mg/day × 12 wk	Completed	Supportive-care endpoints: GPx and phase angle increased; MDA also increased; no attributable SAEs; no antitumor efficacy endpoint.

Notes: Most clinical entries involve conventional RES, dietary sources, micronized formulations, or first-generation formulation enhancements. KB/24/2023 is the only oncology-associated human study in the manuscript involving a commercial liposomal RES formulation, and it evaluated supportive-care rather than antitumor endpoints.

For completeness, three additional registered RES studies merit brief mention as adjacent context, although they do not meet the inclusion criteria for the cancer-trial tally above and are therefore omitted from Table 5. Of these, the most informative is a Phase I trial of a proprietary micellar resveratrol formulation (JOTROL^®; NCT04668274), which evaluated single ascending oral doses (200–700 mg) in healthy volunteers for pharmacokinetics, safety, and food effect.²⁶² This micellar resveratrol formulation constitutes a genuine nanoscale RES delivery system—reportedly achieving roughly nine-fold higher plasma exposure than equivalent doses of unformulated RES—but its registered clinical development is presently directed toward central nervous system and rare-disease indications (Friedreich’s ataxia, mucopolysaccharidosis type 1, Alzheimer’s disease, and MELAS) rather than oncology, and no corresponding cancer trial of this micellar resveratrol formulation has yet been registered. The existence of this advanced nanoformulation in human pharmacokinetic testing nonetheless illustrates that the manufacturing and regulatory feasibility of nano-RES has been demonstrated, reinforcing that the absence of nano-RES from human cancer trials reflects clinical-development priorities rather than insurmountable technical barriers. The remaining two studies are more peripheral: a Phase II randomized controlled trial of a multi-component phytomedicine formulation for cancer-related fatigue (NCT05664009)—containing ginsenosides alongside other plant-derived constituents but not RES as a defined principal ingredient—is evaluating cancer-related fatigue rather than antitumor efficacy in adult cancer patients;²⁶³ and an observational study of resveratrol-enriched wine consumption (NCT05981053) is restricted to healthy aging endpoints and explicitly excludes cancer patients.²⁶⁴ Neither of these latter two studies constitutes a RES anticancer trial and they are recorded here only to document the boundaries of the search.

Translational Barriers

These four barriers are not independent but causally linked: low intrinsic molecular potency raises the bar that nanocarrier delivery efficiency must clear; manufacturing inconsistency confounds the interpretation of nanotoxicology data; and preclinical–clinical efficacy mismatches obscure whether a negative trial reflects formulation failure, EPR variability, or genuine molecular ineffectiveness. Each is examined in turn below.

Inconsistent Translation of Preclinical Efficacy to Human Outcomes

The 2- to 6-fold therapeutic-index enhancements frequently reported in cell-based and rodent xenograft studies of RES nanocarriers have not yet been reproduced in human cancer trials of engineered RES nanoscale systems. Even the completed Warsaw liposomal-RES oncology-associated study reported biochemical activity signals rather than tumor response, progression-free survival, or overall survival. This bench-to-bedside attrition is partly attributable to the cell line-derived xenograft (CDX) models that dominate the preclinical literature.

Three CDX features may inflate apparent nanocarrier performance. First, CDX tumors often show more homogeneous genetics, faster growth, and more permeable neovasculature than clinical tumors, which can overestimate EPR-mediated nanoparticle accumulation. Second, immunodeficient hosts eliminate adaptive immune responses that RES may modulate, thereby obscuring both immune-mediated efficacy and immune-related toxicity. Third, subcutaneous implantation does not reproduce the organ-specific stroma, vascular density, lymphatic drainage, or interstitial fluid pressure that governs nanoparticle biodistribution in clinical tumors. Therefore, reported enhancement ratios should be interpreted as optimistic preclinical estimates, and future studies should incorporate orthotopic, patient-derived, and immunocompetent models to better approximate clinically relevant delivery barriers.

Patient-to-Patient Variability in the EPR Effect

The patient-to-patient variability of the EPR effect represents one of the most underappreciated obstacles to clinical translation of RES nanoformulations, because it converts what was historically treated as a uniform design assumption into a stratification problem that current clinical practice has no robust tools to solve.

The EPR effect, long considered the conceptual cornerstone of cancer nanomedicine, has undergone fundamental reassessment following a landmark study revealing extremely low nanoparticle accumulation rates in solid tumors.^62,265 This poor efficiency reflects the heterogeneity of human tumor vasculature—featuring dense desmoplastic stroma, elevated interstitial fluid pressure, and mature vessels—which contrasts sharply with the highly permeable neovasculature of mouse xenograft models.^63,64 Consequently, future RES nanomedicine development may need to place greater emphasis on active targeting with tumor-associated ligands and localized administration routes (aerosolized or oral delivery) to bypass systemic EPR dependence. The field must reframe EPR as a contributory rather than sufficient targeting mechanism.²⁶⁶

Beyond this low average accumulation, three orthogonal axes of EPR heterogeneity in human tumors warrant explicit critique. (i) Inter-patient heterogeneity: even within a single tumor histology, individual patients exhibit up to 35-fold differences in nanoparticle uptake, as documented by ⁶⁴Cu-labeled liposomal doxorubicin (⁶⁴Cu-MM-302) PET/CT imaging in 19 metastatic HER2-positive breast cancer patients (range 0.52–18.5%ID/kg, independent of systemic plasma exposure)²⁶⁷—a magnitude of variance that no rodent xenograft model can recapitulate. (ii) Intra-tumoral heterogeneity: within a single human tumor, microregional nanoparticle accumulation can vary by more than an order of magnitude between perivascular zones, hypoxic cores, and necrotic regions, producing a profoundly non-uniform drug exposure landscape that compromises both efficacy at “cold” niches and safety at “hot” perivascular cuffs.^268,269 (iii) Inter-lesional heterogeneity: in metastatic disease, primary and metastatic lesions within the same patient frequently exhibit divergent EPR competence owing to differences in vascular maturity, stromal density, and lymphatic drainage, such that a nanocarrier dose calibrated for one lesion may systematically under-dose or over-dose other sites in the same individual.²⁷⁰ These three layers of heterogeneity collectively imply that EPR-dependent passive accumulation cannot be modeled as a single population-level parameter and must instead be reconceptualized as a patient- and lesion-specific stratification problem—a reframing currently impeded by the absence of any validated companion imaging or histopathological biomarker for clinical EPR assessment.^271,272

The implications of EPR heterogeneity are not uniform across the malignancies reviewed herein, but rather vary according to tumor-specific vascular and stromal characteristics. Pancreatic ductal adenocarcinoma, with its exceptionally dense desmoplastic stroma and compressed vasculature, represents the most extreme example of EPR failure,⁶⁴ where nanoparticle extravasation is severely impeded regardless of particle size optimization.⁷⁴ Conversely, highly vascularized tumors such as certain breast cancer subtypes (particularly HER2-amplified) may exhibit more favorable, though still heterogeneous, EPR-mediated accumulation. For colorectal cancer, the direct accessibility of primary tumors via the oral route renders systemic EPR dependence largely avoidable—a strategic advantage that positions CRC as a particularly suitable indication for oral nanoformulations. Similarly, the option of aerosolized pulmonary delivery for lung cancer circumvents the systemic EPR bottleneck entirely. These disease-specific considerations reinforce the central argument of this review: nanocarrier selection must be guided by the unique pathophysiological context of each malignancy rather than by a universal passive targeting assumption.

Because no validated companion biomarker (imaging, histological, or circulating) yet exists to stratify patients by EPR responsiveness, any negative RES-nanocarrier trial will remain confounded by the inability to separate formulation failure from non-EPR-responsive enrollment—lending added strategic weight to active targeting and EPR-bypassing locoregional routes.

Difficulties in Manufacturing and Scaling Up Production

Even when a nanoformulation demonstrates compelling preclinical efficacy and an acceptable preliminary safety profile, the transition from milligram-scale laboratory synthesis to GMP-compliant industrial production constitutes the third major translational barrier, reflecting in significant part the severe Chemistry, Manufacturing, and Controls (CMC) bottlenecks noted above.

For complex multicomponent platforms—particularly lipid-polymer hybrid NPs, actively targeted micelles, and stimuli-responsive architectures—maintaining batch-to-batch reproducibility, strictly controlling the polydispersity index (PDI < 0.2) at industrial scale, and ensuring long-term physical stability during storage remain significant engineering hurdles. Conventional batch manufacturing methods often fail to preserve the narrow size distributions and surface functionalization densities achieved at laboratory scale, producing volume-scale-up products with unacceptable variability in both drug release kinetics and in vivo biodistribution. Compounding these engineering challenges, internationally standardized characterization protocols suitable for regulatory cross-product comparison have not yet been established for advanced RES nanocarriers, complicating both the design of CMC packages for IND submissions and the comparative evaluation of competing formulations within and across institutions. Overcoming these barriers will require platform-specific scalable processes, standardized quality attributes, and GMP-compatible manufacturing strategies.

Carrier-Specific Safety, Exposure Window, and Payload-Related Constraints

The fourth translational barrier involves both carrier-specific safety and payload-related exposure constraints. Although carrier engineering can improve RES delivery, clinical translation still requires product-specific toxicology, pharmacokinetic validation, and definition of a safe exposure window. This section therefore considers nanocarrier-related risks together with the dose-dependent pro-oxidant potential and modest intrinsic clinical potency of RES.

Furthermore, the nanotoxicology of the carriers themselves warrants rigorous and independent scrutiny. Although RES is GRAS, the safety profile of the encompassing nanocarriers is distinct and complex. Inorganic platforms, such as gold nanoparticles or mesoporous silica, face strict regulatory scrutiny regarding their in vivo clearance mechanisms, potential for long-term reticuloendothelial system accumulation, and inherent immunogenicity. Before these advanced RES nanomedicines can enter human trials, comprehensive pharmacokinetic and long-term toxicological profiling of the empty nanocarriers themselves must be established to satisfy stringent regulatory safety requirements.

Beyond the general CMC and nanotoxicological considerations outlined above, a carrier-specific toxicological framework is essential for guiding the clinical prioritization of RES nanomedicines. Organic nanocarriers—including liposomes, PLGA, SLNs, and protein-based NPs (albumin)—generally benefit from established biodegradation pathways and favorable regulatory precedent. PLGA, for instance, undergoes hydrolytic degradation to lactic and glycolic acid, both endogenous metabolites, conferring a well-characterized safety profile validated through decades of clinical use in sutures and implants. Similarly, albumin-based nanocarriers benefit from the clinical success of albumin-bound paclitaxel nanoparticles (nab-paclitaxel), which provides a useful regulatory and manufacturing precedent for albumin-based nanocarriers, although each RES-albumin formulation still requires product-specific efficacy, safety, and quality-control validation.²⁷³ However, even these biocompatible organic carriers warrant scrutiny regarding potential complement activation, dose-dependent hepatic accumulation, and the immunological consequences of repeated administration. Specifically, PEGylated liposomes can trigger complement activation-related pseudoallergy (CARPA) and are susceptible to the accelerated blood clearance (ABC) phenomenon upon repeated dosing.^274,275

Inorganic nanocarriers present a fundamentally different toxicological profile. Gold nanoparticles, while considered biologically inert, are not biodegradable and accumulate primarily in the liver and spleen following systemic administration. Long-term studies in rodent models have reported dose-dependent hepatotoxicity, characterized by elevated serum transaminases and histological evidence of Kupffer cell activation, at cumulative doses relevant to repeated therapeutic administration. Mesoporous silica NPs face analogous concerns: while amorphous silica is generally regarded as biocompatible, the high surface area and reactive silanol groups of mesoporous variants can induce hemolysis, pro-inflammatory cytokine release, and pulmonary fibrosis in inhalation models.²⁷⁶ The absence of efficient renal clearance pathways for particles exceeding 8 nm further complicates the safety assessment of these inorganic platforms, as prolonged tissue residence may potentiate chronic inflammatory responses.²⁷⁷ Collectively, these carrier-intrinsic safety issues indicate that RES nanocarriers should be evaluated not only by antitumor efficacy but also by biodegradability, clearance pathway, immune compatibility, manufacturing reproducibility, and regulatory precedent. Carrier-specific nanotoxicological profiles and clinical-readiness considerations are summarized in Table 6.

Table 6.

Carrier-Specific Nanotoxicological Profiles and Clinical-Readiness Assessment

Carrier	Biodegradability	Primary Safety Concerns	Preclinical Adverse Effects	Clearance Pathway	Regulatory Precedent	Tier
Polymeric NPs (PLGA/PLA/PCL)	Generally yes; polymer hydrolysis/enzymatic degradation	Burst release, acidic degradation products, hepatic accumulation, batch-to-batch scale-up variability	Mild hepatic enzyme changes/injection-site irritation in class literature	Hydrolysis/metabolism then renal/hepatic elimination	High for PLGA/PLA drug products; lower for newer polyesters	Tier 1–2
Lipid–polymer hybrid NPs	Partly biodegradable depending on polymer/lipid composition	Complex CMC, ligand density variability, stimuli-triggered burst release	Carrier-specific data limited; immune and hepatic uptake concerns	MPS uptake plus lipid/polymer degradation	Moderate class precedent; RES-specific LPHNPs remain preclinical	Tier 2
Liposomes/PEGylated liposomes	Yes; phospholipid metabolism	CARPA, accelerated blood clearance, opsonization, storage leakage	Acute hypersensitivity; splenic/hepatic uptake	Phospholipid recycling; PEG renal/hepatic handling	High (eg, PEG-liposomal doxorubicin)	Tier 1
SLNs/NLCs / liquid-crystalline lipid NPs	Yes; lipase-mediated degradation	Polymorphic transitions, drug expulsion, lipid-excipient bioactivity	Usually well tolerated; GI or pulmonary irritation possible at high local dose	Lipase breakdown to fatty acids; hepatic metabolism	Moderate–high (GRAS lipids; LNP precedent)	Tier 1–2
Protein NPs (albumin/zein/casein/sericin)	Yes; proteolysis to amino acids	Batch variability, endotoxin/immunogenicity, source material standardization	Rare hypersensitivity; limited non-albumin tox data	Proteolysis and amino-acid recycling	High for albumin NPs; lower for food-protein oncology carriers	Tier 1 / 2–3
Polysaccharide/chitosan systems	Generally yes; enzymatic degradation/depolymerization	Cationic toxicity, nonspecific mucoadhesion, protein adsorption, variable MW/deacetylation	Mucosal irritation or MPS uptake depending on charge	Enzymatic/GI degradation; renal/hepatic clearance of fragments	Moderate for excipient class; low for RES oncology products	Tier 2
Polymeric micelles/nanogels	Often yes depending on block copolymer/crosslinker	Sub-CMC disassembly, off-target P-gp effects, cationic adsorption, hydrogel residue	Limited tox data; possible renal/BBB transporter effects	Unimer dissociation then hepatic/renal clearance	Moderate for some PTX micelles; low for RES-specific systems	Tier 2
Exosomes/biomimetic carriers	Membrane-derived; biologically degradable	Cargo heterogeneity, oncogenic miRNA/protein transfer, scale-up/QC	Limited tox data; immune modulation possible	Membrane fusion and hepatosplenic clearance	Low; no broadly approved exosome drug product	Tier 3
Cyclodextrin complexes/ nanosponges	Partly biodegradable; renal excretion for soluble CDs	β-CD renal tubular toxicity/cholesterol extraction; nanosponge crosslinker residues	Renal vacuolation for some CDs; SBE-β-CD safer	GI degradation and/or renal filtration	Moderate–high for SBE-β-CD excipients; lower for nanosponges	Tier 1–2 / 3
Metallic NPs (Au/Pd/Ag)	No or limited biodegradation	Hepatosplenic retention, metal ion release (Ag), carrier-derived ROS, long-term disposition	Dose-dependent hepatotoxicity, oxidative stress, immune effects	Retained in liver/spleen; slow or incomplete elimination	Low; experimental oncology nanometals only	Tier 3
Mesoporous silica/MOF/ ZIF-8	Conventional MSN low; organosilica/MOF may be degradable	Hemolysis, cytokine release, granuloma, metal/imidazolate release for MOF	Hemolysis, IL-1β/TNF-α elevation, hepatic granuloma in class literature	Size-dependent renal clearance if ultrasmall; otherwise hepatosplenic	Low; ultrasmall silica imaging precedent does not generalize	Tier 3
Magnetic niosomes/ Fe3O4-based systems	Partial; iron core enters iron metabolism	Iron overload, Fenton ROS, magnetic-field penetration limits	Oxidative stress and hepatic iron deposition possible	Ferritin/transferrin recycling after degradation	Moderate for iron oxide agents; low for RES magnetic niosomes	Tier 2–3

Notes: Clinical Readiness Tiers: Tier 1 = regulatory precedent exists and carrier safety/degradation are comparatively well characterized; Tier 2 = partial precedent or route-specific feasibility but incomplete RES-specific validation; Tier 3 = no mature clinical precedent or major unresolved safety/manufacturing barriers.

A further payload-specific concern is RES’s paradoxical pro-oxidant activity. Efficient nanoparticle-mediated uptake can raise intracellular RES to supraphysiological, ROS-generating levels in tissues adjacent to the tumor; therefore, release kinetics should be designed to sustain therapeutic rather than maximal exposure. This risk assumes distinct cancer-specific dimensions according to the predominant carrier architecture, administration route, and local tissue vulnerability.²⁷⁸

For prostate cancer, receptor-associated polymeric nanoparticles, laminin-receptor-associated Res-PdNPs, intratumorally retained RESV–¹⁹⁸AuNPs, and PO₃-MSN-RES may increase local or intracellular RES exposure. These systems therefore require careful modulation of release kinetics, ligand density, and long-term metal or radionuclide biodistribution to avoid exceeding the antioxidant-to-pro-oxidant threshold in adjacent healthy prostatic epithelium, vascular endothelium, and MPS-associated organs.²⁷⁹ For lung cancer, aerosolized nanoformulations deposit RES directly at the tumor site without systemic dilution, potentially achieving exceptionally high local concentrations in pulmonary epithelial cells; future studies evaluating inhaled RES nanocarriers should incorporate systematic dose-escalation toxicology assessments in healthy lung parenchyma to establish the therapeutic index for this administration route.²⁸⁰ For colorectal cancer, the pH-gated release mechanisms employed by several oral delivery platforms are designed to concentrate RES release within a confined colonic segment, raising the possibility that local drug concentrations may exceed the pro-oxidant threshold and damage normal colonocytes adjacent to the tumor; these considerations support sustained and patient-adaptable release profiles for oral CRC-directed RES systems. Finally, for breast cancer, the convergence of multiple uptake-enhancing mechanisms—including CD44-associated uptake,¹⁹² albumin-related transport,^206,207 P-gp-associated efflux modulation, exosome-mediated intracellular delivery²⁸¹—could cumulatively elevate cytoplasmic RES concentrations to pro-oxidant levels in both malignant and normal mammary epithelial cells, necessitating carrier-specific pharmacokinetic-pharmacodynamic (PK-PD) modeling that accounts for the intracellular delivery efficiency of each platform to define the optimal dosing regimen. These cancer-specific pro-oxidant risks and mitigation strategies are summarized in Table 7.

Table 7.

Cancer-Specific Pro-Oxidant Risk Assessment of RES Nanoformulations

Cancer Type	Predominant Nanocarrier and Route	Specific Pro-Oxidant Risk Mechanism	At-Risk Normal Tissue	PK-PD Endpoint	Recommended Mitigation Strategy
Prostate cancer	FRα-targeted polymeric NPs; Res-PdNPs; RESV-198AuNPs; PO3-MSN-RES (IV / intratumoral / in vitro)	Receptor-associated uptake, metal-core ROS, radionuclide/local retention, or controlled-release intracellular exposure may push RES above antioxidant-to-pro-oxidant threshold	Healthy prostatic epithelium; vascular endothelium; MPS organs for metal carriers	Tumor vs normal prostate intracellular RES exposure; ROS and metal/radionuclide retention	Sustained release; ligand-density optimization; long-term metal/radionuclide biodistribution; normal-cell ROS panels
Lung cancer	Pulmonary NLCs; PMX/RES-LCNPs; ELT/RES-NLCs; EGF/folate LPHNPs; PTX@PRES; CD93-PLGA (inhaled / IV)	Pulmonary deposition, ROS-responsive release, and immune-metabolic delivery can concentrate RES or co-payloads in sensitive lung compartments	Alveolar epithelium, bronchial epithelium, alveolar macrophages, CD8+ T cells	BAL-fluid RES and ROS markers; tumor-to-lung RES ratio; T-cell oxidative-stress readouts	Dose-escalation inhalation toxicology; controlled intracellular release; BAL cytology; immune-cell function monitoring
Colorectal cancer	pH-gated oral PLGA/SLN/chitosan/cyclodextrin/MOF systems; systemic micelles (oral / IV)	Colonic pH-triggered or mucoadhesive retention can create local RES spikes; cationic or inorganic carriers can add membrane/ROS stress	Normal colonocytes, mucus layer, microbiota-adjacent epithelium	Colonocyte intracellular RES Cmax/AUC; 8-OHdG; local free-RES release vs pH	Avoid bolus release; dual-trigger pH/microbial systems; ex vivo colon toxicity; microbiota/pH-stratified testing
Breast cancer	Co-loaded liposomes; SLNs/NLCs; HA micelles; albumin NPs; milk exosomes; Au/Ag/MSNs (IV / local / microneedle)	Multiple uptake-enhancing mechanisms and metal/photothermal components can elevate cytoplasmic RES or ROS in mammary tissues	Normal mammary epithelial cells, cardiomyocytes for DOX combinations, MPS organs	Tumor-to-normal mammary RES exposure; cardiac oxidative markers; metal retention	Carrier-specific PK-PD; compare intracellular free RES across carriers; cardiotoxicity panels for DOX co-delivery; avoid overloading biomimetic systems
Gastric cancer	HA/CD44 PEI-MSN RES/anti-miR21; PEI-FA RES-MSN (IV)	Cationic PEI and non-biodegradable MSN add membrane/ROS stress on top of RES intracellular delivery	Normal gastric mucosa, CD44-expressing gastric stem/progenitor cells	CD44+ tumor vs normal mucosa RES ratio; PEI membrane-stress markers	Lower PEI density; degradable silica alternatives; mucosal oxidative-stress and long-term silica-fate assessment
Glioma / GBM	Tf-RES liposomes; lipid-core nanocapsules; adjacent low-dose RES-Cu strategy (BBB-directed / oral)	TfR-mediated delivery may expose BBB endothelium and neural tissue; RES-Cu deliberately exploits ROS generation	Normal neurons, glia, BBB endothelium	Brain-tissue RES exposure; neuronal ROS markers; TfR tumor/BBB selectivity	Define inverted-U low-dose windows; monitor peri-tumoral neural toxicity; validate tumor-restricted uptake
Hepatocellular carcinoma	Chitosan-TPP RES NPs; RES-GNPs (IV/liver-targeted)	Hepatic concentration and gold-core retention can compound RES pro-oxidant and Kupffer-cell activation risks	Normal hepatocytes, Kupffer cells, sinusoidal endothelium	Tumor-to-normal hepatocyte RES ratio; hepatic ROS/Kupffer activation	Prefer biodegradable systems for repeated dosing; liver histopathology; long-term gold-retention panels
Skin cancer/melanoma	Ultradeformable liposomes, nanocapsules, invasome gel (topical/intradermal)	Topical/local routes bypass dilution and can expose peri-lesional keratinocytes to high RES and ROS	Peri-lesional epidermis, dermal fibroblasts, hair follicles	Skin-layer RES concentration vs depth/time; barrier integrity and 8-OHdG	Constrain application field; controlled-release topical design; peri-lesional oxidative-stress monitoring
Ovarian cancer	Core–shell NPs, combination micelles, albumin/RGD-HSA NPs (IP/IV)	IP or ascites exposure could generate high peritoneal free RES; DOX co-loaded micelles add oxidative burden	Peritoneal mesothelium and serosal surfaces	Peritoneal-fluid free RES vs time; mesothelial ROS/viability	Use smaller controlled-release carriers; IP dose-escalation toxicology; mesothelial injury monitoring
Oral/head and neck cancers	RC-GMN RES/Ce6 PDT NPs; RES/5-FU liposomes; topical chitosan NPs (local/IV)	PDT designs deliberately amplify ROS, while topical mucosal delivery may expose normal oral epithelium	Normal oral/pharyngeal mucosa and salivary epithelium	Mucosal RES/Ce6 ROS flux; field-margin oxidative markers	Confine light/dose; titrate RES:Ce6 ratio; monitor mucosal viability and 8-OHdG
Cervical cancer	HP-β-CD/RES complex; DOX/AuNP + RES combination (formulation-enhanced / in vitro)	Formulation-enhanced cervical exposure or AuNP/DOX combinations may increase ROS in HPV-negative epithelium	Normal cervical/vaginal epithelium and basal cells	Cervical epithelial intracellular RES Cmax; AuNP-associated ROS burst	Sustained rather than burst local exposure; minimize AuNP/DOX-associated oxidative stress in non-malignant epithelium; cervical histopathology
Pancreatic cancer	PVP-stabilized AuNP-RES; magnetic niosomal RES (IV/ locoregional)	Metallic/photothermal or magnetic systems may add ROS while attempting to overcome dense stroma	Normal pancreatic acinar/ductal epithelium and peri-tumoral stroma	Intratumoral vs peri-tumoral RES + metal-ROS exposure; thermal dose map	Orthotopic desmoplastic validation; restrict energy deposition; sustained release; peri-tumoral oxidative panels

Abbreviations: AUC, area under the curve; AuNP, gold nanoparticle; BAL, bronchoalveolar lavage; BBB, blood-brain barrier; CD44, cluster of differentiation 44; Ce6, chlorin e6; Cmax, maximum concentration; DOX, doxorubicin; EE, encapsulation efficiency; FRα, folate receptor alpha; GBM, glioblastoma multiforme; HA, hyaluronic acid; HCC, hepatocellular carcinoma; HP-β-CD, hydroxypropyl-β-cyclodextrin; IP, intraperitoneal; IV, intravenous; LC-MS/MS, liquid chromatography–tandem mass spectrometry; MSN, mesoporous silica nanoparticle; NLC, nanostructured lipid carrier; OSCC, oral squamous cell carcinoma; PDT, photodynamic therapy; PEI, polyethylenimine; PK-PD, pharmacokinetic-pharmacodynamic; PLGA, poly(lactic-co-glycolic acid); ROS, reactive oxygen species; SLN, solid lipid nanoparticle; SPARC, secreted protein acidic and rich in cysteine; Tf/TfR, transferrin / transferrin receptor; ZP, zeta potential.

A second molecular-level limitation sets the upper ceiling on this barrier: the relatively low intrinsic clinical potency of RES itself. Even when intracellular RES concentrations are successfully elevated through nanocarrier-mediated delivery, the molecule’s intrinsic pharmacological activity against most oncogenic signaling pathways remains modest relative to that of approved cytotoxic chemotherapeutics or molecularly targeted agents. Phase I trials at oral doses ranging from 0.5 to 5.0 g/day have generally produced only marginal pharmacodynamic biomarker changes—exemplified by the 5% reduction in Ki-67 reported in NCT00256334 —and human-tissue accumulation studies such as EudraCT 2007–002131-91 in prostate cancer have demonstrated that parent-RES tissue concentrations remain orders of magnitude below those of glucuronide and sulfate conjugate metabolites, even at “pharmacological” 250 mg single doses.

This potency ceiling compounds the nanotoxicity barrier: reaching antiproliferative concentrations may itself force RES into the pro-oxidant regime. The therapeutic window is thus bounded not by the maximal achievable intracellular concentration but by the point at which RES flips between its antioxidant and pro-oxidant identities²⁸² —a fundamental constraint, resolvable by no carrier engineering, on how release kinetics, ligand density, and surface chemistry must be tuned.

Advancing clinical translation requires rigorously distinguishing between nanocarrier-intrinsic toxicity and RES payload-specific toxicity. The termination of the micronized RES trial due to cast nephropathy exemplifies the latter, while CARPA associated with PEGylated liposomes exemplifies the former.²⁴⁰ Therefore, future preclinical safety evaluations must move beyond standard hepatic and renal function panels to routinely incorporate comprehensive immunogenicity assessments, ensuring that carrier-induced adverse events are not conflated with payload toxicity. Alternative first-generation strategies—including transmucosal lozenges²⁵⁹ and phospholipid complexes²⁸³—have improved RES absorption but address only the bioavailability limitation without providing tumor targeting or controlled release capabilities. These observations collectively underscore the imperative for advancing true nanocarrier systems into human evaluations. Future clinical investigations must prioritize safety and efficacy assessments of true nanocarriers (eg, liposomes and SLNs) to fully exploit the therapeutic window of this pleiotropic agent in cancer management.

Future Research Directions

The clinical translation barriers identified above define a clear research agenda for advancing RES nanomedicines from preclinical validation to clinical deployment. The following research directions are organized according to translational immediacy, progressing from near-term engineering and regulatory priorities to longer-term opportunities in combination therapy, clinical-trial design, and computational prioritization.

Standardized Manufacturing and Regulatory Scale-Up

A near-term priority for RES nanomedicine translation is closing the Chemistry, Manufacturing, and Controls (CMC) gap. Complex platforms such as LPHNPs must be reproducibly scaled from laboratory synthesis to GMP-compatible production while preserving critical quality attributes, including particle size, PDI, surface charge, surface functionalization, encapsulation efficiency, drug loading, release kinetics, and storage stability. Batch-to-batch variability in any of these parameters may alter biodistribution, intracellular exposure, and safety interpretation.

Platform-specific scalable manufacturing should therefore be prioritized. For polymeric nanoparticles, continuous-flow microfluidic synthesis can improve control over nanoparticle self-assembly and mixing, helping preserve narrow size distributions and reproducible release profiles at clinically relevant production scales.²⁸⁴ For liposomal and lipid-based formulations, thin-film hydration followed by high-pressure microfluidization has demonstrated scalability to tens of liters per batch while maintaining equivalent quality attributes.^284,285 Future RES nanoformulation studies should report standardized characterization data, including size, PDI, zeta potential, encapsulation efficiency, drug loading, morphology, biorelevant release kinetics, and accelerated stability under ICH-relevant conditions. Such reporting standards would improve cross-study comparison and facilitate regulatory evaluation.

Systematic Nanotoxicology and Safety Evaluation

Future safety evaluation should routinely test empty carriers alongside drug-loaded formulations in validated models to separate nanocarrier-intrinsic from RES payload-related toxicity.^286–288 For inorganic platforms, particularly gold nanoparticles and mesoporous silica, long-term biodistribution and clearance studies extending beyond short efficacy windows remain especially necessary to characterize chronic tissue retention and inflammatory responses.

In parallel, safety assessment must account for the dose-dependent antioxidant-to-pro-oxidant switch of RES. Stimuli-responsive carriers are designed to accelerate release after exposure to acidic pH, elevated intracellular glutathione, enzymatic triggers, or other tumor-associated stimuli. Although this design may increase tumor-cell killing, it may also generate transient intracellular RES exposure spikes in tumor-adjacent normal cells. Therefore, future studies should link release kinetics with intracellular RES concentration–time profiles, ROS-related pharmacodynamic responses, and tumor-to-normal tissue exposure ratios. Carrier-specific PK-PD modeling that integrates ADME behavior with RES dose-response relationships would help optimize therapeutic release while reducing the risk of unintended oxidative injury.²⁸⁹

Synergy with Immunotherapy and Combinatorial Approaches

The convergence of nanomedicine and cancer immunotherapy represents a particularly compelling frontier for RES-based therapeutics. RES has been demonstrated to modulate the tumor immune microenvironment through multiple mechanisms, including the downregulation of PD-L1 expression on tumor cells via inhibition of the STAT3 signaling pathway, enhancement of dendritic cell maturation,²⁹⁰ and promotion of cytotoxic T lymphocyte infiltration.²⁹¹ These immunomodulatory properties suggest that RES nanoformulations could function as potent adjuvants to immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 or CTLA-4 axes. Specifically, the co-delivery of RES with anti-PD-L1 antibodies via engineered nanocarriers may help improve tumor immune responsiveness while protecting the antibody payload from premature degradation. Preliminary evidence from preclinical combination studies indicates that RES enhances the efficacy of anti-PD-1 therapy in melanoma and CRC models by reprogramming tumor-associated macrophages from an immunosuppressive M2 to a tumoricidal M1 phenotype.²⁹² Future investigations should systematically evaluate RES nanoformulation-ICI combinations across cancer subtypes, with particular emphasis on TNBC and microsatellite-stable CRC, where current immunotherapy responses remain suboptimal.

This direction has begun to receive direct experimental support. A 2026 lung-cancer study developed CD93-targeted RES-loaded PLGA nanoparticles and reported remodeling of CD8+ T-cell metabolism through AIF-mediated oxidative phosphorylation in models of lung cancer immunotherapy resistance.¹¹⁷ This evidence strengthens the rationale for positioning RES nanocarriers as immunotherapy adjuvants rather than as standalone cytotoxics.

Combination strategies should also be extended beyond chemotherapy and immunotherapy to include radiotherapy. Mansour et al²⁹³ reported that carboxymethyl chitosan nanoparticles loaded with RES enhanced antioxidant and pro-inflammatory responses and increased the sensitivity of Ehrlich ascites carcinoma-bearing mice to γ-irradiation. Although this model does not correspond directly to the four major solid tumors discussed in Prostate Cancer–Breast Cancer, it provides proof-of-concept that RES nanocarriers may function as radiosensitizing adjuvants. Future studies should therefore evaluate whether tumor-targeted RES nanoformulations can improve radiotherapy response while minimizing oxidative injury in surrounding normal tissues.

AI-Driven Design and Personalized Nanomedicine

Artificial Intelligence-Driven Nanocarrier Design. The empirical, resource-intensive optimization of RES nanocarrier formulations can be accelerated by machine learning (ML) and artificial intelligence (AI).²⁹⁴ Quantitative structure-property relationship (QSPR) models can predict critical quality attributes—particle size, encapsulation efficiency, zeta potential, and release kinetics—from input variables such as polymer molecular weight and lipid composition, drastically reducing experimental iterations for formulation optimization.^295,296 Furthermore, deep learning architectures, particularly graph neural networks and generative adversarial networks, can be leveraged to design novel excipient combinations and surface ligand architectures that maximize tumor-selective accumulation while minimizing off-target toxicity. Physiologically based pharmacokinetic (PBPK) modeling integrated with ML algorithms can also predict in vivo drug release profiles and tissue distribution patterns from in vitro data, potentially bridging the critical gap between preclinical efficacy and clinical pharmacokinetics. The adoption of these computational tools is expected to significantly compress the development timeline and reduce the cost of translating RES nanoformulations from laboratory optimization to GMP-compliant manufacturing.

Personalized Nanomedicine and Biomarker-Guided Therapy. The heterogeneity of tumor biology across individual patients mandates a shift toward personalized nanocarrier selection guided by molecular biomarkers. For example, SPARC expression profiling could identify patients most likely to benefit from albumin-based RES nanoformulations,²⁹⁷ while CD44 overexpression status could direct the use of hyaluronic acid-functionalized micelles.²⁹⁸ The integration of liquid biopsy technologies—including circulating tumor DNA and exosome profiling—with nanocarrier-based therapeutic monitoring could enable real-time assessment of treatment response and facilitate adaptive dosing strategies.²⁹⁹ Additionally, the development of theranostic RES nanoplatforms incorporating imaging moieties, such as gadolinium chelates for MRI or fluorescent probes, would permit simultaneous therapeutic delivery and non-invasive monitoring of nanocarrier biodistribution, enabling clinicians to verify tumor accumulation prior to committing to full therapeutic dosing regimens.

Advanced Preclinical Models

A pervasive methodological limitation that transcends all malignancies reviewed in this work is the near-exclusive reliance on conventional cell line-derived xenograft (CDX) models in immunocompromised (nude or SCID) mice for in vivo efficacy evaluation.^248,300 While CDX models have provided valuable 2- to 6-fold proof-of-concept data, their well-documented deficiencies—homogeneous genetics and over-permeable neovasculature, an immunodeficient host, and a non-orthotopic implantation site —systematically overestimate translational potential. To address these limitations, we propose a tiered preclinical evaluation framework that progresses from orthotopic models to patient-derived xenografts and genetically engineered mouse models according to the translational question being addressed.^63,266 As an immediately implementable improvement, orthotopic implantation—in which tumor cells are engrafted into their organ of origin—should be prioritized over subcutaneous xenografts when evaluating route-specific or organ-specific RES nanocarrier performance, because it better preserves tissue-specific microenvironmental features and enables assessment of clinically relevant routes such as aerosolized delivery for lung cancer and oral delivery for CRC. For translational validation, PDX models can help capture intratumoral heterogeneity, stromal complexity, and inter-patient variability³⁰¹ in therapeutic response—features relevant to biomarker-guided nanocarrier selection. Genetically engineered mouse models (GEMMs), which develop autochthonous tumors in immunocompetent hosts, are particularly valuable for evaluating RES nanoformulation–immunotherapy combinations because they better recapitulate interactions among tumor, stroma, and immune compartments within the native organ microenvironment.³⁰²

In silico Prioritization of RES Nanoformulations

In response to the large and heterogeneous dataset accumulated across RES nanoformulation studies, we further organized the extracted evidence into a semi-quantitative in silico prioritization framework. This analysis was not intended to generate a validated predictive PBPK or machine-learning model, because the included studies differed substantially in carrier composition, administration route, tumor model, release assay, endpoint definition, and pharmacokinetic reporting. Instead, the aim was to transform the available physicochemical, biological, and translational data into a model-readable structure that can guide future computational and experimental prioritization.

Three complementary scores were proposed to convert the heterogeneous RES nanoformulation literature into a more model-readable structure. The model-readiness score evaluates whether each formulation class reports descriptors required for future PBPK, PK-PD, nano-QSAR, or machine-learning analysis, including particle size, PDI, zeta potential, encapsulation efficiency, drug-loading capacity, release kinetics, in vitro cytotoxicity, in vivo efficacy, PK/biodistribution, and safety endpoints. The translational priority score estimates near-term development potential based on material precedent, biodegradability, in vivo efficacy, PK evidence, and manufacturing feasibility. The safety-alert score identifies platforms that may require more stringent PK-PD evaluation because of burst release, high intracellular uptake, rapid stimulus-triggered release, absent normal-cell toxicity data, or insufficient biodistribution information.

Using these criteria, biodegradable and clinically familiar platforms, including PLGA-based nanoparticles, lipid-based nanocarriers, SLNs, and LPHNPs, receive higher near-term translational priority because they combine material precedent with tunable release behavior and scalable manufacturing potential. In contrast, inorganic, magnetic, mesoporous silica, gold-based, and exosome-inspired systems provide attractive functional advantages but require more extensive safety, biodistribution, and quality-control data before robust computational extrapolation is feasible. Importantly, platforms designed for rapid intracellular or stimuli-responsive release should not be prioritized solely on the basis of enhanced cytotoxicity, because excessive intracellular RES exposure may shift RES from an antioxidant or chemopreventive agent to a pro-oxidant cytotoxic compound. Future in silico modeling should therefore integrate carrier descriptors with PK-PD safety thresholds to define an intracellular concentration–time window that maximizes tumor-cell apoptosis while minimizing oxidative injury to adjacent non-malignant tissues.

This framework provides a structured basis for identifying which RES nanocarrier classes are most ready for PBPK, PK-PD, nano-QSAR, or machine-learning development, and which require additional safety, biodistribution, or quality-control data before computational extrapolation. The structure of this prioritization framework is presented in Table 8, and its applied scoring across the principal RES nanocarrier platforms is shown in Table 9.

Table 8.

Semi-Quantitative in Silico Prioritization Framework for RES Nanoformulations

Analytical Dimension	Scoring Basis	Interpretation	Practical Implication
Model-readiness score	Availability of particle size, PDI, ZP, EE, DLC, release kinetics, IC50, in vivo efficacy, PK/biodistribution, and safety data	Whether a formulation has sufficient descriptors for future PBPK, PK-PD, nano-QSAR, or ML modeling	Identifies data-rich platforms suitable for computational modeling and highlights missing descriptors.
Translational priority score	Material precedent, biodegradability, in vivo efficacy, PK evidence, manufacturability, CMC feasibility	Estimates near-term development feasibility rather than absolute efficacy	Prioritizes biodegradable and clinically familiar platforms such as PLGA, lipid-based systems, SLNs/NLCs, albumin systems, and selected LPHNPs.
Safety-alert score	Burst release, high intracellular uptake, stimuli-responsive release, metal/inorganic retention, absent normal-cell toxicity or PK data	Flags risk of excessive intracellular RES exposure and pro-oxidant toxicity	Requires carrier-specific PK-PD modeling and normal-tissue oxidative-stress testing before translational claims.
Route-specific modeling need	Oral, IV, inhaled, topical, intratumoral, intraperitoneal, or BBB-directed administration	Determines physiological compartments and barriers to model	Colorectal cancer requires GI/colonic models; lung requires pulmonary deposition and BAL models; systemic administration requires PBPK and tumor-transport models; and brain-directed delivery requires BBB models.
Cancer-specific modeling need	Prostate, lung, CRC, breast, gastric, glioma, HCC, skin, ovarian, oral, cervical, pancreatic	Accounts for vascularity, stromal density, receptor expression, local route access, and microenvironment	Supports disease-specific carrier selection instead of one-size-fits-all ranking.

Table 9.

Applied Semi-Quantitative Scoring of Principal RES Nanocarrier Platforms

Nanocarrier Platform	Model-Readiness Score	Translational Priority Score	Safety-Alert Score
Polymeric NPs	High for PLGA/PCL rows; medium for newer polyesters	High (Tier 1–2; biodegradable and scalable with microfluidic potential)	Low–Medium (burst release and hepatic accumulation require control)
Liposomes	High (size/EE/in vivo data available for several cancer models)	High (Tier 1; strong liposomal oncology precedent)	Low–Medium (CARPA, ABC, and repeat-dose issues)
SLNs / NLCs / lipid crystalline NPs	High for formulation descriptors; medium for tumor PK	High (Tier 1–2; GRAS lipids and route adaptability)	Low–Medium (polymorphism, high local pulmonary/topical exposure)
Lipid–polymer hybrid NPs	Medium–High (good size/EE/release/in vivo data in NSCLC examples)	Medium–High (promising but complex CMC and ligand/stimuli validation needed)	Medium (rapid stimuli-triggered release and intracellular exposure spikes)
Protein NPs (albumin/zein/casein/sericin)	Medium–High for albumin; medium for food-protein systems	High for albumin; medium for zein/casein/sericin (Tier 1 / 2–3)	Low–Medium (immunogenicity and batch/source variability)
Polysaccharide/chitosan systems	Medium (many in vitro; some in vivo co-delivery/radiosensitizing data)	Medium–High for oral/local systems	Medium (cationic adsorption and nonspecific uptake)
Cyclodextrin complexes/ nanosponges	Medium (strong solubility/stability descriptors; fewer in vivo oncology data)	Medium–High for inclusion complexes; medium for nanosponges	Medium (renal/cholesterol extraction risk for some CDs; crosslinker QC)
Polymeric micelles/ polyprodrug NPs	Medium (size/IC50 data common; PK and safety variable)	Medium (micelle precedent exists, but RES systems preclinical)	Medium (sub-CMC disassembly and off-target transporter effects)
Biomimetic/exosome/cell-derived systems	Medium (promising in vitro/in vivo evidence but limited descriptors/QC)	Low–Medium (scale-up and cargo control unresolved)	Medium–High (heterogeneous cargo, uptake routes, MDR claims unvalidated)
Metallic NPs (Au/Pd/Ag)	Medium (size/ZP/in vitro/in vivo data for selected systems)	Low (Tier 3; non-biodegradable and no RES-metal clinical precedent)	High (retention, ion release, ROS, and long-term disposition)
Mesoporous silica/MOF / ZIF-8	Medium–Low (pore/release data; sparse systemic PK/safety)	Low (Tier 3; biodegradation and regulatory uncertainty)	High (hemolysis/cytokines, silica/MOF fate, granuloma risk)
Magnetic niosomes/iron-oxide-based systems	Low–Medium (early cell-based RES evidence)	Medium–Low (iron-oxide precedent does not validate RES magnetic niosomes)	Medium (iron overload, Fenton ROS, magnetic-field constraints)

Conclusion

The global burden of cancer necessitates continued exploration of therapeutic agents and delivery strategies that may complement conventional modalities while reducing systemic toxicity and drug resistance. RES has emerged as a distinguished pleiotropic phytochemical, exhibiting potent antioxidant, anti-inflammatory, and antineoplastic properties across a spectrum of malignancies. Despite its promising molecular mechanisms—ranging from the modulation of p53 and NF-κB pathways to the suppression of EMT—the clinical utility of free RES is severely compromised by its poor aqueous solubility, photosensitivity, and rapid and extensive metabolism driven by glucuronidation and sulfation in the liver and intestines, leading to negligible systemic bioavailability.

Nanotechnology provides a rational strategy for improving the pharmaceutical and delivery limitations of RES. Encapsulation within nanocarriers can enhance RES stability, apparent solubility, release control, and tumor-associated exposure in preclinical models. Active targeting strategies using ligands such as folic acid, hyaluronic acid, and anti-PSMA antibodies may further improve receptor-associated cellular uptake in selected tumor contexts, although their in vivo performance remains dependent on protein-corona formation, tumor heterogeneity, and administration route. In addition, pH- or redox-sensitive systems and co-delivery platforms combining RES with agents such as doxorubicin or paclitaxel have shown potential for improving combination efficacy and modulating MDR-associated pathways, including P-gp-related drug efflux.

A key insight emerging from the comparative analyses conducted across four major malignancies is that optimal nanocarrier selection should be guided by disease-specific therapeutic imperatives rather than a universal platform approach. For prostate cancer, biodegradable polymeric systems incorporating active targeting or stimuli-responsive release appear to be among the most translationally informative architectures, although in vivo validation remains limited. For lung cancer, carrier selection may need to consider the intended route and disease setting, including pulmonary-adapted lipid systems for local delivery, polymeric micelles or hybrid nanoparticles for systemic MDR-oriented strategies, and inorganic nanohybrids for selected theranostic applications. For colorectal cancer, oral colon-targeted systems should emphasize gastrointestinal stability and site-specific release, whereas systemic or metastatic disease may still benefit from receptor-associated targeting. For breast cancer, subtype-guided carrier selection remains particularly important: RES-loaded SLNs and PCL-based polymeric nanoparticles, albumin-based systems, co-loaded liposomes, HA-modified micelles, and biomimetic exosomes each appear most relevant to different preclinical delivery problems rather than to a single universally superior platform. This disease-stratified nanocarrier framework may help guide future preclinical prioritization and, after further validation, inform the design of early-phase clinical studies.

Despite encouraging preclinical findings, clinical translation remains limited. Future development should prioritize reproducible manufacturing, long-term carrier-specific safety, biomarker-guided patient selection, and evidence that engineered RES nanocarriers provide advantages beyond conventional RES formulations. While animal studies consistently report tumor regression and metastasis inhibition, human clinical trials remain scarce and are largely confined to micronized formulations rather than advanced engineered nanomedicines. The termination of the Phase II micronized RES trial due to renal toxicity underscores the complex safety profile of high-dose formulations and highlights the need for rigorous toxicology profiling of novel carriers. Future research efforts must therefore prioritize bridging this “bench-to-bedside” gap by focusing on the reproducible scale-up of nanocarriers, comprehensive long-term safety evaluations in humans, and the design of clinical trials that stratify patients based on specific biomarkers. Ultimately, successful translation will depend on whether selected RES nanoformulations can demonstrate reproducible manufacturing, acceptable long-term safety, clinically meaningful pharmacokinetic advantages, and disease-specific efficacy beyond conventional RES formulations.

Funding Statement

This study was supported by the National Natural Science Foundation of China (No. 82575065); Sichuan Provincial Special Program for Central Government-Guided Local Science and Technology Development (No. 24ZYZYTS0310); Science and Technology Project of the Sichuan Provincial Health Commission (No. 24LCYJPT14); Special Research Program for Traditional Chinese Medicine of the Sichuan Provincial Administration of Traditional Chinese Medicine (No. 2024ZD027); and the “Foundation Strengthening” Action Plan of Chengdu University of Traditional Chinese Medicine (No. 2023-42).National Natural Science Foundation of China (No. 82575065); Sichuan Provincial Special Program for Central Government-Guided Local Science and Technology Development (No. 24ZYZYTS0310); Science and Technology Project of the Sichuan Provincial Health Commission (No. 24LCYJPT14); Special Research Program for Traditional Chinese Medicine of the Sichuan Provincial Administration of Traditional Chinese Medicine (No. 2024ZD027); and the “Foundation Strengthening” Action Plan of Chengdu University of Traditional Chinese Medicine (No. 2023-42).

Author Contributions

Huifang Yang conceived of the presented idea. Huifang Yang wrote the manuscript with support from Zilin Cheng. Kexin Tang, Yilin Wang and Tongtong Zeng analyzed the data. Jing Guo supervised the findings of this work. All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors declare no conflicts of interest in this work.