Smart nanoparticle delivery systems for curcumin: a targeted strategy to enhance anticancer efficacy and bioavailability

Abstract

Curcumin, a natural polyphenol derived from Curcuma longa, exhibits potent multimodal anticancer activity by modulating critical oncogenic pathways (e.g., NF-κB, STAT3, PI3K/Akt/mTOR), inducing apoptosis, suppressing angiogenesis, and reversing multidrug resistance (MDR). However, its clinical translation is severely hindered by poor aqueous solubility, rapid metabolism, and negligible oral bioavailability (typically <1% in serum), which result in subtherapeutic concentrations at tumor sites. Smart nanoparticle delivery systems have emerged as a transformative strategy to overcome these limitations, enabling enhanced solubility, controlled release, and targeted accumulation in tumors. This review comprehensively summarizes the advancements in curcumin-loaded nanocarriers, including polymeric nanoparticles (e.g., PLGA, chitosan), lipid-based systems (e.g., liposomes, NLCs), inorganic nanoparticles (e.g., mesoporous silica, gold nanoparticles), and stimuli-responsive platforms (pH-, redox-, enzyme-sensitive). These nanosystems leverage passive targeting via the enhanced permeability and retention (EPR) effect and active targeting through ligand conjugation (e.g., folate, transferrin, hyaluronic acid), significantly improving tumor-specific delivery and curcumin’s bioavailability—exemplified by a 178-fold increase in plasma AUC in healthy human volunteers following oral administration of the co-grinding formulation CUMINUP60® compared to standard crystalline curcumin. Preclinical and clinical studies demonstrate that nanoformulated curcumin synergizes with conventional chemo/radiotherapy, sensitizes resistant cancers, and modulates the immunosuppressive tumor microenvironment. For instance, Phase I/II trials indicate that formulations like nanomicellar curcumin (Sinacurcumin®) can modulate inflammatory cytokines, while liposomal variants (Lipocur™) have shown target engagement in metastatic cancers, albeit with the need for dose optimization. Hybrid nanocarriers co-delivering curcumin with chemotherapeutics or siRNA further augment therapeutic outcomes in models of colorectal, breast, pancreatic, and glioblastoma cancers. Despite these progresses, the gap between preclinical success and clinical translation remains significant. This review critically analyzes the barriers impeding commercialization, specifically highlighting the heterogeneity of the EPR effect, the lack of scalable GMP-compliant manufacturing for complex nanocarriers, and the regulatory hurdles regarding long-term biocompatibility and safety assessments.

Graphical Abstract

Introduction

Cancer remains a devastating global health challenge, with GLOBOCAN 2022 estimating 19.96 million new cases and 9.74 million deaths annually, where lung, breast, and colorectal cancers collectively account for over 30% of both incidence and mortality [1]. Conventional chemotherapy faces significant limitations including systemic toxicity, development of multidrug resistance (MDR), and inadequate tumor selectivity, which collectively compromise therapeutic efficacy and patient quality of life [2, 3]. These shortcomings underscore the urgent need for safer, more targeted therapeutic alternatives. Curcumin, a naturally occurring polyphenol derived from Curcuma longa, has emerged as a promising multimodal anticancer agent. Its mechanisms include induction of apoptosis through caspase activation, suppression of angiogenesis via VEGF inhibition, modulation of critical signaling pathways (NF-κB, MAPK, JAK/STAT), and regulation of reactive oxygen species (ROS) [4]. Notably, curcumin exhibits broad-spectrum activity against drug-resistant malignancies and demonstrates synergistic effects with conventional chemo/radiotherapy, potentially reversing MDR phenotypes [5].

Despite its therapeutic promise, curcumin’s clinical translation is severely hampered by profound pharmacokinetic challenges. It exhibits extremely poor aqueous solubility (<11 ng/mL), undergoes pH-dependent degradation, and is susceptible to rapid photoisomerization and hydrolysis [6]. Pharmacologically, it suffers from negligible oral bioavailability (<1%) due to extensive first-pass metabolism involving glucuronidation and sulfation, coupled with a short plasma half-life (~30 min) [7]. These limitations result in subtherapeutic drug concentrations at target sites. Metabolic studies reveal that curcumin undergoes rapid phase I reduction (forming dihydrocurcumin and tetrahydrocurcumin) and phase II conjugation, with these metabolites demonstrating altered biological activities compared to the parent compound [8]. Consequently, unmodified curcumin fails to achieve therapeutic plasma concentrations even at high doses (e.g., 8 g/day in clinical trials) [9].

Nanotechnology offers transformative solutions to overcome these barriers. Encapsulation within nanocarriers significantly enhances solubility through hydrophobic interactions and molecular encapsulation [10]. Passive targeting leverages the enhanced permeability and retention (EPR) effect, where nanoparticles (NPs) extravasate through the leaky vasculature of tumors and are retained due to impaired lymphatic drainage [11, 12]. Advanced nanocarrier systems include liposomes, polymeric nanoparticles (PLGA, chitosan), dendrimers, micelles, and inorganic hybrids (e.g., silica-lipid composites), which collectively comprise >99% of reported delivery platforms [13]. These systems not only improve pharmacokinetic profiles but also protect curcumin from degradation, extending systemic circulation time [14].

“Smart” nanocarriers represent the frontier of precision oncology, incorporating stimuli-responsive elements for spatiotemporal drug release. pH-responsive systems exploit the acidic tumor microenvironment (pH 5.5–6.8 versus physiological pH 7.4) using ionizable groups (amines, carboxylates) or acid-labile linkages (hydrazones, acetals) that trigger drug release upon protonation or bond cleavage [15, 16]. Enzyme-responsive carriers utilize tumor-overexpressed proteases (MMP-2/9, cathepsins) by incorporating cleavable peptide substrates that undergo enzymatic hydrolysis in the tumor microenvironment, releasing the payload [17–19]. Dendrimer-based systems, particularly polyamidoamine (PAMAM) dendrimers, enable high drug-loading capacity and facilitate nuclear targeting in cancer cells [20]. These intelligent designs enhance tumor-specific accumulation while minimizing off-target effects, thereby improving therapeutic indices [21, 22].

Recent preclinical and clinical studies demonstrate the efficacy of nanoformulated curcumin. Lipocur™ (liposomal curcumin) and Sinacurcumin® (nanomicellar formulation) have shown improved bioavailability and antitumor activity in clinical trials [23]. Phase I/II trials for various cancers (NCT04480502, NCT02465285) are evaluating liposomal curcumin in combination with radiotherapy or chemotherapy, with preliminary data indicating enhanced tumor suppression and reduced toxicity [24]. Nano-curcumin synergizes with chemotherapeutic agents (e.g., 5-Fluorouracil, doxorubicin) by sensitizing resistant cancer cells through downregulation of survival pathways like survivin and STAT3 [25, 26]. Hybrid nanocarriers co-delivering curcumin with siRNA (e.g., against survivin) demonstrate augmented tumor penetration and synergistic apoptosis induction in ovarian and cervical cancer models [27].

Despite promising advances, challenges remain in clinical translation. The EPR effect exhibits significant heterogeneity in human tumors compared to rodent models, necessitating patient stratification strategies [28, 29]. Scalability and reproducibility of nanocarrier manufacturing, along with long-term biocompatibility assessments, require further optimization [30]. Future research should focus on multifunctional “theranostic” nanoparticles combining imaging capabilities with targeted delivery, personalized formulations based on tumor biology, and combinatorial regimens leveraging nano-curcumin’s chemosensitizing properties [31, 32]. With continued innovation, smart nanodelivery systems hold immense potential to unlock curcumin’s full anticancer potential, transforming it from a dietary compound into a precision oncology therapeutic.

Curcumin and its anticancer mechanisms and advantages

Curcumin, the principal bioactive polyphenol derived from Curcuma longa, exerts multifaceted anticancer effects through the simultaneous modulation of critical oncogenic signaling pathways and epigenetic regulators [33, 34]. As illustrated in Fig. 1, its antitumor efficacy is driven by pleiotropic actions at both molecular and cellular levels: downregulating pro-survival factors (e.g., Bcl-2, Bcl-xL), inhibiting proliferation pathways (e.g., NF-κB, PI3K/Akt/mTOR, STAT3), inducing cell cycle arrest, and promoting programmed cell death [35, 36].

Fig. 1.

Illustration of main antitumor mechanisms of curcumin

Central to its mechanism is the potent inhibition of the STAT3 and NF-κB signaling axes, which are pivotal drivers of tumor proliferation, survival, and metastasis [37–39]. Curcumin prevents the phosphorylation and nuclear translocation of these transcription factors, thereby suppressing the expression of downstream genes such as Survivin, VEGF, and MMP-9 [40, 41]. Concurrently, it disrupts the PI3K/Akt/mTOR cascade, balancing the interplay between apoptosis and protective autophagy, which often culminates in synergistic cell death in resistant cancer models [33, 42]. Recent studies have further elucidated novel mechanisms, highlighting curcumin’s ability to induce ferroptosis via the regulation of lipid peroxidation and the ACSL4 axis [43–46], as well as its role in modulating the tumor microenvironment (TME) [47–49].

Beyond specific signaling targets, curcumin exhibits broad-spectrum activity against multidrug resistance (MDR) [50–52]. It functions as a reversal agent by competitively inhibiting P-glycoprotein (P-gp) efflux pumps and transcriptionally suppressing MDR1 expression via the AP-1 and NF-κB axes [51–53]. Curcumin enhances the cytotoxicity of conventional chemotherapeutics (e.g., doxorubicin, cisplatin, and oxaliplatin) by restoring intracellular drug accumulation, disrupting the Bcl-2/Bax equilibrium, and inhibiting COX-2 signaling [36, 53, 54]. Similarly, in glioblastoma, curcumin induces autophagic cell death via Akt/mTOR inhibition, while in pancreatic cancer, it targets constitutively active NF-κB to sensitize tumors to gemcitabine [55, 56]. Epigenetically, curcumin acts as a natural inhibitor of histone deacetylases (HDACs), promoting histone acetylation and reactivating silenced tumor suppressor genes such as p53 and p21 [57, 58]. These diverse molecular actions underscore curcumin’s therapeutic versatility, although its clinical application relies heavily on advanced delivery strategies to overcome pharmacokinetic barriers [33, 59].

Barriers to clinical application and physicochemical challenges

Physicochemical barriers

Curcumin, a polyphenolic compound with the chemical formula C₂₁H₂₀O₆, exhibits pronounced hydrophobicity (log P ≈ 3.2) and low aqueous solubility, which severely restricts its dissolution and bioavailability in physiological environments [24]. Its stability is critically compromised under physiological pH (7.4), where it undergoes rapid alkaline hydrolysis through nucleophilic attack on the α,β-unsaturated β-diketone moiety. This degradation follows first-order kinetics, with studies demonstrating that over 78% of free curcumin decomposes within 20 min at pH 7.4–8.0, yielding vanillin, ferulic acid, and cyclopentadiene derivatives as primary breakdown products [60, 61]. The degradation rate inversely correlates with acidity; curcumin remains relatively stable below pH 6.5 but becomes highly labile in neutral-to-alkaline conditions due to deprotonation of phenolic groups, which disrupts its conjugated diene structure and accelerates autoxidation [62, 63].

Compounding this instability, curcumin is susceptible to photoisomerization under UV/visible light exposure. Recent molecular dynamics simulations reveal that UV-A irradiation (350 nm) induces trans-cis configurational changes at the C═C double bonds in the heptadienone linker, generating photoisomers that serve as precursors for photodimerization via [2 + 2] cycloaddition or photooxidation (H₂-loss) pathways [64]. This photochemical reactivity not only diminishes curcumin’s bioactivity but also complicates experimental reproducibility, as uncontrolled light exposure during handling can artifactually alter its pharmacological profile [65]. The dual vulnerability to pH-dependent hydrolysis and photoisomerization results in a plasma half-life of less than 10 min in vivo, drastically curtailing its therapeutic efficacy [66].

To overcome these challenges, nanotechnology-driven delivery systems have emerged as indispensable strategies. Nanoencapsulation within liposomes, polymeric nanoparticles, or lipid-based carriers physically shields curcumin from hydrolytic enzymes and ambient light while enhancing dispersibility [10]. For instance, liposomal encapsulation in phosphatidylcholine bilayers or polymeric matrices like PLGA (poly(lactic-co-glycolic acid)) creates a hydrophobic microenvironment that stabilizes the keto-enol tautomer—the pharmacologically active form of curcumin [67]. Surface functionalization of nanocarriers with targeting ligands (e.g., folic acid) further exploits tumor microenvironment features (e.g., acidic pH, overexpressed receptors) to facilitate selective cellular uptake and reduce off-target degradation [68]. Notably, studies have confirmed that nanoemulsions and solid lipid nanoparticles (SLNs) elevate curcumin’s aqueous solubility by >10,000-fold. For instance, Wang et al. demonstrated that optimized SLNs extended the half-life to >24 h and achieved a 26-fold increase in oral bioavailability in rats compared to unformulated curcumin suspensions [69, 70]. These advances underscore nanotechnology’s pivotal role in transforming curcumin from a labile phytochemical into a viable anticancer agent.

Biological and anatomical barriers

Curcumin faces significant tissue-specific barriers that impede therapeutic efficacy. In glioblastoma (GBM) [71], the blood-brain barrier (BBB) restricts curcumin penetration into tumor sites. The BBB comprises tight-junction endothelial cells, pericytes, and astrocytes that collectively limit paracellular diffusion of macromolecules. While GBM disrupts some BBB integrity, invasive tumor regions often retain functional efflux transporters like P-gp, which actively expels curcumin. Consequently, therapeutic concentrations in brain tumors remain suboptimal, undermining curcumin’s potential to modulate pathways like p53 and JAK/STAT in GBM [72, 73].

Simultaneously, safety concerns regarding high-dose administration present another limitation. High-dose free curcumin exhibits dose-dependent hepatotoxicity, mechanistically arising from mitochondrial dysfunction, ROS overproduction, and activation of necroptosis pathways involving RIPK1/RIPK3 complexes in hepatic cells [74]. Clinical reports note elevated serum ALT/AST levels in some patients consuming >8 g/day of unformulated curcumin [75]. This necessitates a delicate balance between achieving therapeutic concentrations and avoiding systemic toxicity.

To address these multifaceted challenges—ranging from poor aqueous solubility and rapid metabolism to anatomical barriers and toxicity—advanced nanoparticle delivery systems have emerged as a transformative solution. These nanoformulations (e.g., liposomes, polymeric NPs) not only enhance pharmacokinetics but also actively modulate the tumor microenvironment (TME) by inhibiting myeloid-derived suppressor cells (MDSCs) and cancer-associated mesenchymal stromal cells (MSCs) [76, 77]. Similarly, TME-responsive nanoplatforms utilize stimuli like hypoxia, redox imbalance, and enzymatic activity to achieve precise drug release [78]. Recent advancements include solvent-free co-grinding formulations (e.g., CUMINUP60®), which elevate the plasma AUC of curcumin in healthy volunteers by 178-fold following oral administration compared to standard extracts, primarily through improved dissolution and metabolic stability [79]. These strategies not only enhance bioavailability but also facilitate the co-delivery of curcumin with chemotherapeutics, as seen in nanomicelles loaded with doxorubicin and curcumin, which effectively reverse MDR in lung cancer [80].

Advanced nanostrategies to overcome limitations

Curcumin’s therapeutic potential in oncology is significantly constrained by its intrinsic physicochemical limitations, particularly its extremely poor aqueous solubility and susceptibility to alkaline degradation [81]. As summarized in Table 1, specific nanocarrier platforms have been developed to directly counteract not only physicochemical barriers but also biological hurdles such as poor tissue penetration and drug resistance. While the specific mechanisms of targeting and efficacy are detailed in sections “Smart nanocarriers for curcumin delivery” and “Curcumin-loaded nanomedicines in cancer therapy”, this table provides a comprehensive overview of the quantifiable improvements achieved across all these domains. Encapsulation within lipid-based and supramolecular nanostructures has emerged as a primary strategy; liposomes provide bilayer sequestration that enhances solubility while preserving membrane permeability advantages [82], whereas polymeric micelles (e.g., Pluronic/PCL systems) achieve solubilization capacities up to g/L ranges through hydrophobic core entrapment [83]. Cyclodextrin complexes, particularly those employing γ-cyclodextrin derivatives, leverage macrocyclic cavities to form inclusion complexes that improve solubility by orders of magnitude while protecting the labile β-diketone moiety from hydrolytic degradation [84, 85].

Table 1.

Comparative summary of curcumin’s barriers and nanocarrier-mediated improvements

Physicochemical barrier	Baseline value/characteristic (curcumin)	Nanocarrier strategy	Quantifiable improvement	Reference
Aqueous solubility	Extremely low (<11 ng/mL); Hydrophobic	Cyclodextrin Complexes	1237-fold increase in solubility.	[84]
		Solid Lipid NPs (SLNs)	>10,000-fold increase in aqueous solubility.	[69, 70]
Systemic stability	Rapid degradation at physiological pH	PLGA Nanoparticles	Colloidal stability maintained for >1 month.	[97]
		Liposomes	Significant protection from hydrolysis (stabilizes keto-enol form).	[67]
Oral bioavailability	Negligible (<1%)	Co-grinding formulation	178-fold increase in plasma AUC (in humans).	[79]
		PLGA nanoparticles	22-fold increase in oral bioavailability (in rats).	[97]
		Solid Lipid NPs (SLNs)	26-fold increase in oral bioavailability (in rats).	[70]
		NLCs	11.93-fold increase in oral bioavailability.	[108]
Tissue targeting	Poor accumulation; BBB restriction	Transferrin-conjugated NPs	8-fold increase in brain concentration.	[206, 207]
		HA-decorated Liposomes	3.3-fold higher tumor drug accumulation.	[178–180]
Tumor penetration	Limited diffusion in dense stroma	RGD-Albumin NPs	200% improvement in stromal diffusion.	[193]
Therapeutic efficacy	Drug resistance/High dose req.	Au-Curcumin conjugates	56–73% enhancement in radiation sensitivity.	[133]
		CUR-DOX PLGA NPs	3-fold higher apoptosis rate vs. monotherapy.	[223]

Stabilization innovations address curcumin’s rapid metabolic and photochemical degradation. PEGylation creates steric hydration barriers that reduce opsonization and extend systemic circulation by >10-fold—critical for tumor accumulation via the EPR effect [86]. Concurrently, antioxidant co-loading (e.g., vitamin E TPGS) synergistically enhances oxidative stability while acting as an emulsifier in PLGA nanoparticles, where its amphiphilic structure simultaneously inhibits peroxyl radical-mediated degradation and improves cellular uptake [87, 88]. pH-responsive systems, such as Eudragit S100-coated liposomes, further prevent gastric degradation while enabling targeted colonic release, demonstrating >98% encapsulation efficiency and controlled payload retention [89].

Bioavailability enhancement leverages both lipidic and crystalline nanoarchitectures. Self-emulsifying drug delivery systems (SEDDS) generate nanoemulsions (<50 nm) spontaneously upon intestinal exposure, facilitating lymphatic transport that bypasses hepatic first-pass metabolism [90]. Recent SEDDS formulations increase oral bioavailability by 1.4–4.3-fold through mixed micelle-mediated solubilization and P-gp inhibition [91]. Nanocrystal technology concurrently addresses dissolution limitations; particle size reduction to 200–500 nm amplifies saturation solubility by 26-fold and dissolution velocity via the Noyes-Whitney equation [92], while surface adhesion to intestinal mucosa prolongs residence time. Solidified SNEDDS and nanocrystal-embedded oral films now enable dose reduction while maintaining pharmacokinetic advantages, as evidenced by fenofibrate nanocrystals showing 1.8-fold higher AUC_0-∞ [93].

These nano-strategies collectively enhance therapeutic indices in preclinical oncology models. Cyclodextrin-curcumin complexes exhibit 1237-fold solubility improvements enabling prolonged tumor suppression, while albumin-coated liposomes extend half-life and potentiate cytotoxicity in cisplatin-resistant cancers [84]. Clinical translation is accelerating, with >210 trials investigating nanoformulated curcumin—including phase II studies of micellar curcumin for pancreatic cancer and lipid-polymer hybrids for colorectal malignancies [94, 95]. Nevertheless, industrial scalability and regulatory hurdles remain, particularly concerning long-term stability of colloidal systems and carrier metabolite toxicology [96]. Future development requires rational integration of multifunctional designs—such as PEGylated cyclodextrin-liposome hybrids—to harmonize solubilization, stabilization, and targeted delivery within a single platform.

Nanocarrier platforms and smart strategies for curcumin delivery

Current nanocarrier strategies can be broadly categorized into two dimensions: the foundational material platforms (e.g., polymers, lipids, inorganic matrices) and the functionalization strategies used to impart ‘smart’ capabilities (e.g., stimuli-responsiveness, active targeting). This section first reviews the major carrier types and subsequently discusses the advanced functionalization strategies applied to them (Fig. 2).

Fig. 2.

Advantages of curcumin-loaded nanoparticle delivery systems for enhanced anti-tumor therapy

Polymeric nanoparticles

The development of smart nanoparticle delivery systems represents a transformative strategy to overcome the intrinsic limitations of curcumin—a potent natural compound with multifaceted anticancer properties—including its extremely poor aqueous solubility, rapid systemic metabolism, and consequent low oral bioavailability. Among polymeric nanocarriers, poly(lactic-co-glycolic acid) (PLGA) nanoparticles stand out due to their exceptional biocompatibility, biodegradability, and tunable drug release kinetics. Recent advancements demonstrate that PLGA encapsulation significantly enhances curcumin’s pharmacokinetic profile; notably, PLGA nanoparticles have been shown to increase oral bioavailability in Wistar rats by up to 22-fold compared to unformulated curcumin, primarily by protecting the payload from gastric degradation and facilitating intestinal absorption [97]. This is achieved through optimized fabrication techniques like emulsion-solvent evaporation, yielding particles with sizes around 145 nm, a zeta potential of approximately −21.8 mV, and encapsulation efficiencies reaching 94% in optimized formulations, while maintaining colloidal stability for at least 1 month under physiological conditions [97]. The release kinetics are governed by a combination of diffusion through the polymer matrix and polymer relaxation, allowing for sustained delivery. Beyond bioavailability enhancement, PLGA nanocarriers enable targeted delivery to tumor sites. For instance, surface modification with Tet-1 peptide facilitates blood-brain barrier penetration for glioblastoma and Alzheimer’s therapy, while PLGA-TPGS (d-α-tocopheryl polyethylene glycol succinate) nanoparticles exhibit preferential accumulation in hepatocellular carcinoma (HepG2) cells, significantly improving antitumor efficacy and reducing systemic toxicity in vivo [98, 99]. Recent work in 2024 further highlights PLGA-curcumin’s role in mitigating diabetic nephropathy by inhibiting renal apoptosis via Bcl-2 protein modulation [100].

Beyond synthetic polymers, chitosan-based nanoparticles leverage unique bioadhesive properties and positive surface charge to enhance mucoadhesion and prolong gastrointestinal residence time, critical for improving curcumin absorption. Chitosan-gum arabic hybrid nanoparticles, in particular, demonstrate enhanced cellular uptake in colorectal cancer models compared to free curcumin, leading to superior tumor suppression through prolonged cellular exposure and reduced IC50 values [101]. The protonation of chitosan’s amine groups in the acidic tumor microenvironment or upon endosomal internalization (the “proton sponge” effect) promotes endosomal escape, ensuring efficient intracellular curcumin delivery [102]. This mechanism underpins the efficacy of chitosan-curcumin nanoparticles (CUR-CS-NP) in colorectal cancer, where they significantly downregulate pro-inflammatory NF-κB signaling and inhibit foam cell formation [103]. Innovations include thiolated chitosan for improved permeation and composite systems like chitosan-eugenol-curcumin nanoconjugates, which exhibit synergistic cytotoxicity against colon cancer cells while inducing DNA fragmentation and apoptosis [104]. Gelatin-based nanocarriers, recognized for their high biocompatibility and FDA approval status, offer another proteinaceous platform for controlled curcumin release. Their gel-forming capability allows precise modulation of release profiles, making them suitable for sustained delivery applications in tissue regeneration and localized cancer therapy. However, challenges remain in maintaining gelatin’s physicochemical stability across varying biological environments, particularly concerning solubility modulation and long-term storage stability, which are active areas of investigation [105].

Collectively, polymeric nanocarriers (PLGA, chitosan, gelatin) provide versatile platforms to enhance curcumin’s therapeutic index. PLGA excels in bioavailability enhancement and controlled release, chitosan leverages mucoadhesion and tumor microenvironment responsiveness, and gelatin offers exceptional biocompatibility for sustained delivery. While significant progress has been made in optimizing encapsulation efficiency, stability, and targeted delivery, ongoing research focuses on refining stimuli-responsive behaviors (e.g., pH-, enzyme-, or redox-triggered release), improving tumor-specific accumulation through advanced surface functionalization, and conducting comprehensive long-term toxicity assessments to accelerate clinical translation [10]. The convergence of material science and nanomedicine continues to drive innovations in these smart delivery systems, holding substantial promise for unlocking curcumin’s full anticancer potential.

Lipid-based nanocarriers

Among lipid-based nanocarriers, solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) have demonstrated remarkable efficacy in enhancing lymphatic uptake and drug payload capacity. SLNs, composed of solid lipids, provide a stable matrix that protects curcumin from degradation and enables controlled release. However, NLCs—a second-generation system blending solid and liquid lipids—address critical limitations of SLNs, such as drug expulsion during storage and limited loading capacity. The imperfect crystalline structure of NLCs allows for higher drug encapsulation (up to 90–99%) and significantly curtails premature leakage, thereby optimizing therapeutic delivery [106, 107]. In vivo studies underscore the superiority of NLCs; for instance, Fang et al. reported that curcumin-loaded NLCs enhanced oral bioavailability (with an AUC increase of up to 11.93-fold) compared to free curcumin, attributed to improved solubilization, prolonged gastric residence, and enhanced intestinal adhesion [108]. Furthermore, several in vitro and in vivo evaluations demonstrated that NLC encapsulation significantly extended the plasma half-life of curcumin, maintaining therapeutic concentrations for a longer duration compared to the rapid elimination of free curcumin [109, 110]. Moreover, in prostate cancer xenograft models, NLCs reduced tumor volume by 40% through enhanced cellular uptake and sustained apoptosis induction, without systemic toxicity [111].

The enhanced bioavailability of lipid-based systems stems from multifaceted mechanisms. Lipid nanoparticles activate biliary and pancreatic secretions, promoting lipid digestion and micelle formation, which facilitates curcumin absorption [112]. Their nano-scale size (typically 10–200 nm) and surface properties enable uptake through enterocytes via clathrin-mediated endocytosis or macropinocytosis, while hydrophobic interactions with chylomicrons further direct them to lymphatic circulation, evading hepatic metabolism [113]. Comparative analyses reveal that NLCs outperform SLNs in lymphatic targeting due to their optimized particle size (ideally <100 nm) and negative zeta potential, which prolong residence in Peyer’s patches and enhance M-cell-mediated translocation [114].

Beyond synthetic lipid systems, biomimetic nanocarriers like liposomes and exosomes leverage natural targeting mechanisms. Liposomes, with phospholipid bilayers mimicking cell membranes, encapsulate curcumin within hydrophobic or aqueous compartments, improving stability and enabling surface functionalization for active targeting [115]. Exosomes, endogenous nanovesicles derived from cells, offer superior biocompatibility and low immunogenicity. Engineered exosomes loaded with curcumin achieve approximately 5-fold higher plasma concentrations in murine models than free curcumin and exhibit innate tropism toward inflammatory or tumor sites [116]. For example, macrophage-derived exosomes deliver curcumin to activated monocytes, reducing inflammation in LPS-induced septic shock models and suppressing tumor growth via enhanced permeability and retention (EPR) effects [117, 118]. Recent innovations include exosomes functionalized with targeting ligands (e.g., RGD peptides or GE11), which further refine tumor-specific delivery through receptor-mediated endocytosis [119, 120].

Despite these advancements, clinical translation faces challenges, including scalable production, long-term stability, and regulatory hurdles. While lipid-based carriers dominate current research due to their manufacturability and proven efficacy, exosome-based systems require standardized isolation and loading protocols to ensure batch consistency [121]. Ongoing clinical trials focus on optimizing these nanoplatforms, with hybrid approaches—such as exosome-liposome fusions—emerging as promising strategies to synergize natural targeting with high drug-loading capacity [122].

In conclusion, lipid-based and biomimetic nanocarriers have revolutionized curcumin delivery, transforming a molecule with poor bioavailability into a potent anticancer agent. NLCs, with their enhanced payload and lymphatic targeting, and exosomes, with their innate biocompatibility and precision, exemplify the convergence of material science and biology in advancing targeted cancer therapy.

Inorganic nanoparticles

Mesoporous silica nanoparticles (MSNs) represent a cornerstone in inorganic nanocarrier design for curcumin delivery, leveraging their highly ordered honeycomb-like porous architecture with tunable pore diameters typically ranging from 2 to 10 nm [123]. This structural specificity directly governs drug release kinetics: larger pore dimensions accelerate molecular diffusion, substantially reducing the release half-life by minimizing steric hindrance and surface adsorption effects [124, 125]. The exceptional drug-loading capacity (>700 m²/g surface area and >0.6 cm³/g pore volume) stems from their vast internal surface decorated with abundant silanol groups, enabling efficient adsorption of hydrophobic curcumin molecules irrespective of aqueous solubility limitations [126, 127]. Surface functionalization strategies—particularly amine grafting—further optimize payload retention and sustained release profiles. For instance, amine-functionalized MSNs with 4.7 nm pores demonstrated 8.8% cumulative curcumin release, significantly exceeding the 1.5% observed in smaller-pore (1.8 nm) analogs, underscoring the critical role of pore size in release modulation [128]. Recent advances in 2024 have elucidated how pore geometry influences not only release kinetics but also cellular internalization pathways and immunomodulatory responses, highlighting the multifactorial optimization required for precision oncology applications [129].

Beyond silica-based systems, gold nanoparticles (AuNPs) offer distinct therapeutic advantages through photothermal conversion capabilities. When irradiated with near-infrared (NIR) light, AuNPs undergo localized surface plasmon resonance, generating hyperthermia (42–45 °C) that selectively ablates tumor cells while sparing healthy tissues [130, 131]. This photothermal effect synergizes with curcumin’s chemotherapeutic action: AuNP-curcumin conjugates disrupt mitochondrial membrane potential, amplify reactive oxygen species (ROS) generation, and downregulate oncogenic pathways (VEGF, STAT-3) more effectively than either modality alone [132]. A 2024 preclinical study on cervical cancer demonstrated that Au-curcumin nanocomposites enhanced radiation sensitivity by 56–73%, achieving tumor regression through dual DNA damage potentiation and heat-shock protein inhibition [133]. The combinatorial approach addresses curcumin’s pharmacokinetic limitations—rapid systemic clearance and enzymatic degradation—while exploiting AuNPs’ deep-tissue NIR penetrance (up to 1 cm) for spatially controlled therapy [134, 135].

Comparative analyses of inorganic nanocarriers reveal trade-offs between functionality and biocompatibility. While quantum dots offer optical tracking capabilities, cadmium-based variants pose toxicity risks due to heavy metal leaching [136]. Iron oxide nanoparticles enable magnetic targeting but may accumulate in reticuloendothelial organs, causing oxidative stress [137]. MSNs exhibit superior biocompatibility and renal clearance when surface-modified with polyethylene glycol (PEG), though their degradation kinetics require careful calibration to prevent silicon accumulation [138, 139]. Gold nanoparticles, while generally biocompatible, necessitate rigorous size control (<20 nm) to avoid aggregation-induced embolism. Current biocompatibility assessments employ high-resolution imaging (scanning probe microscopy) to monitor nanocarrier-cell interactions and quantitative ROS assays to predict inflammatory sequelae [140]. Ongoing clinical evaluations (e.g., NCT04818333, NCT05516524) focus on translating these inorganic platforms into targeted curcumin delivery systems that balance anticancer efficacy with systemic safety [24].

Having discussed the foundational material platforms (polymers, lipids, and inorganic matrices), the following sections focus on the functionalization strategies—specifically stimuli-responsiveness and active targeting—that upgrade these carriers from passive vehicles to ‘smart’ nanomedicines.

Functionalization strategy I: stimuli-responsive systems

Stimuli-responsive nanocarriers represent a pivotal advancement in targeted curcumin delivery, leveraging distinct pathological cues within tumor microenvironments to achieve site-specific drug release with minimized off-target effects. pH-sensitive systems exploit the acidic extracellular conditions of tumors (pH 6.5–7.0), which differ markedly from physiological pH (7.4). These carriers typically utilize polymers functionalized with ionizable groups (e.g., carboxyl or amine moieties) that undergo protonation-deprotonation transitions, triggering conformational changes or degradation of acid-labile bonds (e.g., hydrazone or acetal linkages) to release curcumin [141]. For instance, chitosan-alginate nanoparticles synthesized via aerosol-assisted methods exhibit pH-dependent swelling in acidic environments, enhancing curcumin release in tumor sites [142]. Similarly, carboxymethyl cellulose/starch/reduced graphene oxide composites demonstrate accelerated drug elution under acidic conditions due to protonation-induced matrix relaxation [143]. Recent innovations include lysine-functionalized mesoporous silica hybrids, which optimize pH-triggered release kinetics while improving cellular uptake [144].

Redox-responsive systems capitalize on elevated glutathione (GSH) levels (2–10 mM) in tumor cells versus normal tissues (2–20 μM). These carriers incorporate disulfide bonds (-S-S-) that undergo cleavage in reductive intracellular compartments, facilitating cytosolic curcumin release. Redox-active nanomaterials, such as disulfide-crosslinked polymeric micelles or liposomes, enhance tumor specificity by exploiting GSH gradients [145, 146]. For example, polyplexes with disulfide bonds enable rapid payload release upon exposure to intracellular reductases, significantly improving therapeutic indices in drug-resistant cancers [147]. Recent studies highlight dual redox/enzyme-responsive liposomes that synergistically degrade via phospholipase A2 and GSH, augmenting curcumin bioavailability and suppressing oxidative stress in cancer cells [148]. Inorganic hybrids also leverage this mechanism; for instance, Au-curcumin conjugates designed to release their payload in the reductive tumor environment have been shown to enhance radiation sensitivity by up to 73%, effectively coupling chemotherapy with radiotherapy [133].

Enzyme-activated carriers target overexpressed proteases like matrix metalloproteinases (MMPs) in tumor stroma. MMP-cleavable peptide sequences (e.g., GPLG, PVGLIG) are engineered into nanogel backbones, enabling enzymatic hydrolysis and localized drug liberation [149, 150]. A 2024 study demonstrated MMP-2-responsive peptide hydrogels that disintegrate upon enzyme contact, releasing encapsulated curcumin to inhibit pancreatic tumor progression, resulting in a 40% reduction in tumor volume in preclinical evaluations [151]. Similarly, gelatin-based dual stimuli-responsive hydrogels incorporate MMP-sensitive linkers alongside pH-sensitive groups, achieving cascaded drug release in response to tumor-specific enzymatic and acidic cues [152, 153]. This strategy minimizes premature leakage while maximizing intratumoral accumulation.

Multi-stimuli responsive nanoplatforms integrate complementary triggers (e.g., pH/redox, pH/enzyme) to overcome limitations of single-stimulus systems. pH/redox dual-responsive polyplexes exhibit “cascade” release: acidic pH induces nanoparticle swelling and endosomal escape, followed by GSH-triggered disulfide cleavage for cytoplasmic curcumin delivery [154]. Thermo/pH-sensitive poly(N-isopropylacrylamide-co-allylamine) nanogels expand under hyperthermia (40 °C) and acidic pH, enhancing drug penetration in hypoxic tumors [153]. Such systems demonstrate 3–5-fold higher bioavailability than monoresponsive carriers by exploiting synergistic microenvironmental triggers [155].

These smart nanocarriers substantially enhance curcumin’s anticancer efficacy by improving pharmacokinetics, tumor accumulation (via EPR effect), and cellular internalization. Nanoencapsulation protects curcumin from rapid metabolism, extending systemic circulation and enabling passive targeting [156]. Recent clinical translations emphasize stimuli-responsive designs as promising strategies to overcome curcumin’s poor solubility and bioavailability, paving the way for next-generation targeted cancer therapies [157].

Functionalization strategy II: active targeting strategies

Active targeting strategies represent a pivotal advancement in nanocarrier systems for curcumin delivery, specifically designed to overcome the limitations of passive accumulation by exploiting receptor-mediated endocytosis pathways. Ligand-conjugated nanoparticles, such as those functionalized with folate, transferrin, or aptamers, exhibit enhanced specificity toward tumor cells overexpressing corresponding receptors. Folate receptors (FRα) are frequently overexpressed in epithelial cancers (e.g., ovarian, breast), enabling folate-decorated nanocarriers to selectively deliver curcumin while minimizing off-target effects [158]. Similarly, transferrin receptors (TfR) are upregulated in metastatic cancers; transferrin-conjugated systems facilitate cellular uptake and can bypass multidrug resistance mechanisms by evading P-gp efflux [159]. Aptamers—single-stranded DNA/RNA oligonucleotides selected via SELEX—offer high binding affinity, low immunogenicity, and superior tumor penetration compared to antibodies. Recent innovations include aptamer-siRNA chimeras for combinatorial gene silencing and curcumin delivery, demonstrating enhanced cytotoxicity in prostate cancer models [160].

Hyaluronic acid (HA)-functionalized nanocarriers exemplify precision targeting for colorectal cancer, where CD44—a transmembrane glycoprotein linked to cancer stemness, metastasis, and chemoresistance—is abundantly overexpressed. HA-modified nanoparticles exploit CD44-mediated endocytosis to boost cellular internalization and tumor accumulation. For instance, HA-grafted PLGA micelles loaded with doxorubicin (as a model therapeutic) showed 118.2 nm diameters and 7.2% drug loading, achieving significantly higher cytotoxicity in CD44 + HCT-116 colon cancer cells than in non-tumor cells [161]. In vivo studies corroborate this: curcumin-loaded HA/TPGS nanoparticles radiolabeled with ⁹⁹ᵐTc revealed preferential biodistribution to tumors via SPECT/CT imaging, underscoring HA’s role in enhancing tumor-specific delivery [162]. This strategy not only amplifies curcumin’s anticancer efficacy but also reduces systemic toxicity by limiting exposure to healthy tissues.

Comparative analyses highlight context-dependent advantages of ligand selection. Folate targeting excels in FRα-high cancers (e.g., ovarian), where folate-PEG-g-polyaspartamide micelles co-delivering cisplatin and curcumin exhibit synergistic effects and extended survival in xenograft models. Transferrin ligands, however, prove more effective against TfR-rich, aggressive tumors, particularly in overcoming drug efflux mechanisms. Dual-ligand systems—e.g., folate and transferrin-decorated polymeric magnetic nanoparticles—further optimize specificity and uptake. These co-deliver curcumin with 5-fluorouracil (5FU), generating pH-responsive, sustained release and hyperthermia-enhanced apoptosis, with combination indices as low as 0.2–0.35 confirming potent synergy [163]. Such systems exemplify how multiplexed targeting addresses tumor heterogeneity and resistance.

Emerging biomimetic approaches push these frontiers further. Biomimetic exosomes engineered with HA or aptamers via genetic or chemical modifications enhance active targeting while evading immune clearance [164]. Additionally, platelet membrane-camouflaged nanoparticles incorporating prostaglandin E2 (PGE2) demonstrate dual targeting and reparative functions in ischemic injury models, suggesting translatability for metastatic sites [165]. Despite promise, scalability, long-term biocompatibility, and ligand stability during circulation require optimization. Future work should prioritize in vivo validations of multi-ligand curcumin nanoformulations, especially in CD44+ colorectal metastases, to translate lab efficacy into clinical oncology tools [166] (Tables 2).

Table 2.

Stimuli-responsive mechanisms for targeted curcumin release

Stimulus type	Trigger in tumor microenvironment/external source	Carrier design feature	Release kinetics/mechanism	Efficacy in preclinical models	Reference
pH-sensitive	Extracellular pH 6.5–7.0; endosomal pH 5.0–6.0	Ionizable groups (amines/carboxylates); acid-labile linkages (hydrazones)	3-fold faster release at pH 5.0–6.0 vs. pH 7.4	~50% tumor regression in breast cancer (Cur@HFn nanocages)	[238]
Redox-sensitive	High intracellular GSH (2–10 mM)	Disulfide crosslinked polymers (-S-S-)	Rapid cleavage in reductive environments	73% enhanced radiation sensitivity (Au-curcumin conjugates)	[133]
Enzyme-responsive	Overexpressed MMP-2/9, cathepsins	Cleavable peptide substrates (e.g., GPLG, PVGLIG)	Enzymatic hydrolysis-driven release	40% tumor volume reduction (MMP-2-responsive hydrogels)	[151]
Multi-stimuli	pH + redox; pH + enzyme	Combined ionizable groups and disulfide bonds	Cascaded release (e.g., pH-triggered swelling → redox cleavage)	3–5-fold higher bioavailability vs. monoresponsive systems	[155]
External Stimuli (Light/Magnetic)	NIR Light; Magnetic Field	AuNPs (SPR effect); SPIONs (Magnetic targeting)	Photothermal-triggered release; Magnetic guidance & heating	60% tumor suppression in colorectal cancer (Dual-labeled SPIONs)	[249]

Curcumin-loaded nanomedicines in cancer therapy

Colorectal cancer

The application of curcumin-loaded nanomedicines in colorectal cancer (CRC) therapy has demonstrated substantial preclinical and clinical promise, leveraging advanced delivery systems to overcome inherent bioavailability limitations. In preclinical models, curcumin encapsulated in MPEG-PCL micelles (25 mg/kg) achieved a 50% reduction in tumor volume in C26 murine colon carcinoma xenografts, attributed to its exceptional encapsulation efficiency (99%) and drug loading capacity (12.95%) [167]. Notably, NLCs generally exhibit superior bioavailability (e.g., 12-fold enhancement) and tumor suppression compared to PLGA (9.2-fold), owing to their lipid-based architecture that enhances intestinal absorption and lymphatic transport [168, 169].

Clinically, curcumin nanoformulations combined with conventional chemotherapy regimens have yielded encouraging outcomes. In a Phase II trial (NCT02439385) involving 44 patients, nanostructured lipid carriers (G-NLC) co-administered with FOLFIRI/Bev (Folinic acid, Fluorouracil, and Irinotecan/Bevacizumab) in metastatic CRC patients reported a median progression-free survival (PFS) of 12.8 months and overall survival (OS) of 30.7 months. Tumor response rates included 20% partial response (PR) and 63.6% disease control rate(DCR), underscoring the role of nanocarriers in potentiating chemotherapeutic efficacy [170, 171]. Furthermore, the randomized Phase IIa CUFOX trial revealed that curcumin combined with FOLFOX significantly improved OS (Hazard ratio (HR): 0.339, p = 0.016) compared to chemotherapy alone (HR: 0.571, p = 0.200). Notably, the objective response rate (ORR) was significantly higher in the curcumin group (53.3%) compared to the control group (11.1%, p = 0.039). This OS advantage may stem from curcumin’s ability to modulate inflammatory pathways like NF-κB and STAT3 and synergize with cytotoxic agents to enhance apoptosis [172].

Recent innovations focus on refining targeted delivery mechanisms to optimize tumor-specific accumulation. Folate-functionalized nanoparticles, such as FA-PEG-CUR-SPC NPs, exploit overexpressed folate receptors on CRC cells, enhancing cellular uptake and reducing off-target effects. These systems exhibit pH-responsive release, with drug liberation at tumor sites (pH 6.4) occurring threefold faster than in systemic circulation (pH 7.4), thereby maximizing local drug concentration. Additionally, enzyme-sensitive designs (e.g., matrix metalloproteinase-triggered NPs) and immunotargeted approaches (e.g., anti-L1-CAM antibody-conjugated diatomite nanoparticles) further augment tumor selectivity and mitigate multidrug resistance mechanisms common in CRC [173, 174]. Despite these advances, challenges persist, including scalable production and long-term toxicity profiles. Nevertheless, the integration of nanocarriers with biocompatible materials (e.g., cellulose nanocrystals) and real-time biodistribution monitoring holds transformative potential for CRC therapy [175, 176].

In summary, nanoengineered curcumin delivery systems represent a paradigm shift in CRC treatment, enhancing bioavailability, tumor targeting, and therapeutic synergy with conventional regimens. Ongoing clinical evaluations and innovative nanoplatforms continue to bridge translational gaps, promising improved patient outcomes.

Breast cancer (triple-negative focus)

The application of hyaluronic acid (HA)-decorated liposomes for curcumin delivery represents a cutting-edge strategy to overcome the therapeutic challenges of triple-negative breast cancer (TNBC), a subtype characterized by the absence of estrogen, progesterone, and HER2 receptors, which limits treatment options and portends a poor prognosis. TNBC frequently exhibits overexpression of CD44 receptors, particularly in cancer stem-like cells (CSCs) that drive tumor initiation, metastasis, and chemoresistance [177]. In the context of TNBC, leveraging the HA-CD44 targeting strategy described in section “Functionalization strategy II: active targeting strategies” is particularly advantageous due to the dense overexpression of CD44 on TNBC cells and cancer stem-like cells (CSCs). By exploiting this receptor-mediated endocytosis, HA-decorated liposomes achieved 3.3-fold higher tumor accumulation compared to free curcumin [178–180].

Preclinical studies using MDA-MB-231 xenograft models demonstrate the potency of this approach. HA-curcumin liposomes achieve approximately 70% suppression of pulmonary metastasis, attributed to dual mechanisms: direct cytotoxicity against bulk tumor cells and disruption of CSC self-renewal [181]. The formulation inhibits key oncogenic pathways, including RhoA/ROCK and PI3K/Akt signaling, which are hyperactivated by CD44-HA interactions in metastatic TNBC. This downregulates anti-apoptotic proteins (e.g., Bcl-2, XIAP), metastasis-promoting factors (e.g., MMP-9, VEGF), and transcription factors like NF-κB, thereby inducing apoptosis and suppressing epithelial-mesenchymal transition (EMT) [182]. Additionally, by targeting CD44+ CSCs, the system reduces aldehyde dehydrogenase (ALDH)-positive populations and tumor-initiating capacity, crucial for preventing recurrence.

Beyond metastasis control, HA-curcumin liposomes enhance bioavailability—a critical hurdle given curcumin’s poor solubility and rapid metabolism. Encapsulation protects curcumin from degradation, prolongs systemic circulation, and leverages the enhanced permeability and retention (EPR) effect for passive tumor accumulation. When combined with HA’s active targeting, this results in 3.3-fold higher tumor drug concentrations compared to free curcumin [183, 184]. In vivo, this translates to significant primary tumor regression (>50% volume reduction) and reduced metastatic burden in lung tissue, validated by histopathology and bioluminescent imaging [185].

Comparative studies highlight advantages over other nanocarriers. While polymeric nanoparticles (e.g., PLGA) and micelles also improve solubility, HA-liposomes exhibit superior CD44-specific cellular uptake and deeper tumor penetration. For instance, pH-sensitive liposomes show efficacy but lack active targeting [186]. Magnetic nanoparticles enable external guidance yet face biocompatibility concerns [187]. HA-liposomes further outperform non-targeted liposomes, as PEGylation alone fails to enhance intracellular delivery despite prolonging circulation [182]. Dual-coated systems (e.g., PEG-HA liposomes) optimize both stealth properties and targeted uptake, achieving 1.7-fold higher tumor inhibition than passive carriers [186].

Despite promise, challenges remain. HA molecular weight influences binding affinity; high-MW HA (175–350 kDa) optimizes CD44 engagement but accelerates blood clearance, necessitating dosage refinement [188]. Future directions include co-delivery with chemotherapeutics (e.g., paclitaxel) to exploit curcumin’s chemosensitizing effects and hybrid systems integrating photothermal agents for multimodal therapy [185]. Clinical translation awaits rigorous toxicity profiling, though HA’s biocompatibility and curcumin’s safety up to 8 g/day in trials support feasibility [189].

In summary, HA-decorated liposomes harness CD44 overexpression in TNBC to deliver curcumin with precision, simultaneously eradicating bulk tumor cells and CSCs while mitigating metastasis. This paradigm exemplifies how nanotechnology transforms natural compounds into targeted oncotherapeutics.

Pancreatic cancer

The therapeutic landscape of pancreatic ductal adenocarcinoma (PDAC) is dominated by a dense desmoplastic stroma and a hypoxic, immunosuppressive tumor microenvironment (TME) that severely limits drug penetration. While early polymeric formulations such as NanoCurc™ established the foundational feasibility of systemic curcumin delivery in preclinical models [190, 191], specifically extending median survival from 28 to 63 days in xenograft models, recent researches have pivoted toward “smart” multifunctional nanocarriers designed to actively breach these stromal barriers and reprogram the TME [192].

Recent advances focus on co-delivery systems that leverage synergistic interactions to disrupt the stromal matrix. For instance, a study developed RGD-peptide modified human serum albumin (HSA) nanoparticles for the co-delivery of gemcitabine and curcumin (RGD-HSA-GEM/CUR) [193]. This system demonstrated a 200% improvement in drug diffusion through the stroma compared to free drug combinations by downregulating fibrosis-associated proteins and inhibiting cancer-associated fibroblasts (CAFs). By targeting integrin receptors, these nanoparticles not only facilitated deep tissue penetration but also suppressed MDR1 and BCL-2 expression, effectively sensitizing resistant PDAC cells to chemotherapy [194].

Furthermore, breakthroughs in 2024 have integrated biomimetic technology with nanozymes to address the hypoxic nature of PDAC. Li et al. engineered a metal-organic framework (MOF) nanosheet decorated with platinum nanozymes to deliver curcumin [195]. This platform functions as a catalase mimic, converting intratumoral hydrogen peroxide (H₂O₂) into oxygen (O₂) to alleviate hypoxia, thereby amplifying the efficacy of photodynamic therapy (PDT). Such “oxygen-generating” strategies represent a significant leap from passive carriers, actively modulating the metabolic TME to enhance curcumin-mediated cytotoxicity.

Beyond stromal and hypoxic barriers, recent investigations (2023–2025) have highlighted the capacity of curcumin nano-systems to reverse the “cold” immune microenvironment of PDAC. Novel mannose-modified liposomal formulations co-loading curcumin and immunoadjuvants have shown remarkable efficacy in repolarizing tumor-associated macrophages (TAMs) from the pro-tumorigenic M2 phenotype to the anti-tumor M1 phenotype [196]. This repolarization restores the secretion of pro-inflammatory cytokines (e.g., TNF-α, IL-12) and recruits cytotoxic T lymphocytes into the tumor core, suggesting that curcumin nanomedicines can effectively synergize with immune checkpoint inhibitors to overcome PDAC immunosuppression.

In parallel, emerging gene-chemotherapy combinations address the genetic drivers of PDAC. Polyplex nanoparticles developed in 2019 co-delivering curcumin and siRNA targeting the KRAS oncogene (mutated in >90% of PDAC cases) have shown promise [197, 198]. These systems utilize curcumin not just as a cytotoxic agent, but as a bioactive carrier stabilizer that enhances endosomal escape, leading to simultaneous KRAS silencing and apoptosis induction [199, 200]. Collectively, these recent studies illustrate a paradigm shift from simple encapsulation to the engineering of TME-responsive, stroma-penetrating nanomedicines that unlock curcumin’s potential in refractory pancreatic cancer.

Glioblastoma

The therapeutic application of curcumin in glioblastoma (GBM) has been significantly limited by its poor bioavailability and solubility, as well as the restrictive blood-brain barrier (BBB) [201]. While early research established curcumin’s ability to modulate core oncogenic pathways—such as NF-κB, PI3K/Akt/mTOR, and STAT3—to suppress glioma proliferation [63], recent research has pivoted towards engineering nano-delivery systems designed to overcome these pharmacokinetic barriers and enhance efficacy.

Nanocarriers have proven effective in encapsulating curcumin without compromising its bioactivity, promoting its uptake by GBM cells, and enhancing its cytotoxic and pro-apoptotic effects [202]. For instance, curcumin-loaded niosomal nanoparticles demonstrated superior anti-tumor effects against glioblastoma stem-like cells (GSCs) compared to free curcumin in vitro, showing high encapsulation efficiency and sustained release [202]. Similarly, dendrosomal curcumin nanoformulation effectively inhibited proliferation and induced apoptosis in U87MG glioblastoma cells by downregulating pluripotency genes via miR-145 activation [203]. Nanodisk (ND) systems, particularly when combined with ApoE, have also been shown to significantly enhance curcumin delivery and intracellular concentration in GBM cells [204].

The overarching strategy of these nano-systems is to achieve targeted delivery. Reviews highlight that nano-formulations such as nanoparticles, liposomes, and polymeric carriers can improve curcumin’s solubility, absorption, and penetration into GBM cells [205]. Mechanisms such as receptor-mediated transcytosis (RMT) allow functionalized nanocarriers to interact with endothelial cell surface receptors, thereby facilitating BBB traversal and subsequent drug release. Functionalizing nanoparticles with Tf ligands exploits this endogenous transport mechanism, significantly enhancing brain biodistribution. Preclinical studies demonstrate that Tf-conjugated nanocarriers—such as gold nanoparticles, PEGylated albumin nanoparticles, and porous silicon nanoparticles—achieve up to an 8-fold increase in brain curcumin concentrations compared to non-targeted formulations. Correspondingly, in vivo efficacy studies in U87MG xenografts revealed that these transferrin-conjugated systems could reduce tumor growth by approximately 45% compared to free curcumin controls, validating the relevance of targeted delivery [206, 207]. This targeted delivery was validated in in vitro BBB models, where Tf-nanoparticle uptake was concentration- and time-dependent, with specificity confirmed through competitive inhibition assays using free Tf antibodies.

Furthermore, innovative approaches like conjugating curcumin with antibodies (e.g., CD68) have been explored to direct the compound to tumor-associated microglia, showing anti-tumor activity in models [208]. Beyond pure therapeutic delivery, the concept of combining diagnostics and therapy (theranostics) is emerging. More advanced nano-strategies, including biomimetic systems, are part of the evolving research landscape aimed at improving BBB traversal and tumor accumulation [209]. Additionally, alternative delivery routes such as nose-to-brain administration are being investigated as non-invasive methods to bypass the BBB entirely, as suggested in reviews discussing future directions. Finally, the integration of curcumin nanoformulations with standard chemotherapy like temozolomide is a promising avenue to modulate multiple signaling pathways and enhance anti-cancer effects, as indicated by preclinical studies.

However, it is crucial to note that while numerous preclinical studies demonstrate efficacy, clinical trials specifically for curcumin-based nano-therapies in GBM remain scarce, highlighting a critical gap between laboratory research and clinical application [207].

Other cancers

Lipid-polymer hybrid nanoparticles (LPNs) and other nanocarrier systems have demonstrated exceptional potential in enhancing the anticancer efficacy and bioavailability of curcumin across diverse carcinomas, particularly in lung, prostate, and hepatic cancers. These advanced delivery platforms address curcumin’s inherent limitations—poor solubility, rapid metabolism, and systemic instability—by improving tumor-specific accumulation and cellular uptake through passive targeting (EPR effect) and active ligand-mediated strategies.

In lung cancer, cationic lipid nanosystems significantly enhance curcumin’s anti-proliferative and pro-apoptotic effects. For instance, curcumin-loaded solid lipid nanoparticles (Cur-SLNs) optimized for A549 cells exhibit superior cytotoxicity and cellular uptake compared to free curcumin, achieving >80% encapsulation efficiency (EE) and inducing 60–75% apoptosis [210]. Liposomal formulations like PlexoZome® further suppress migration, colony formation, and cancer-marker protein expression in vitro, while hybrid systems co-loaded with paclitaxel or triptolide amplify tumor inhibition through synergistic pathways [211]. Recent innovations include pH-sensitive, EGFR-targeted LPNs that co-deliver erlotinib and Bev, enhancing tumor targeting and overcoming chemoresistance in NSCLC models [212].

For prostate cancer, nanocarriers overcome docetaxel resistance in castration-resistant models. Curcumin nanoparticles (CUR NPs) formulated with Miglyol 812 and TPGS restore potency in DU145 and PC3-resistant cells by inhibiting P-gp efflux, with 90% EE and sustained cytotoxicity [213]. Aptamer-functionalized LPNs co-delivering curcumin and cabazitaxel further improve tumor targeting and anti-proliferative activity in PC3 cells [214]. Meta-analyses confirm dose-dependent tumor suppression in animal models, where high-dose nanocurcumin downregulates PCNA/MMP2 mRNA and upregulates pro-apoptotic Bax [215]. Additionally, antibody-conjugated formulations (e.g., CD44 or HER2-targeted NPs) enhance cellular internalization and biodistribution, extending plasma half-life by 5.3-fold in murine xenografts [216].

In hepatocellular carcinoma (HCC), multifunctional nanoplatforms leverage molecular self-assembly and peptide targeting. SP94 peptide-modified nanoparticles co-loaded with curcumin and resveratrol significantly improve drug retention, reduce required dosages, and delay release kinetics, achieving synergistic tumor growth inhibition without off-target toxicity [106]. Similarly, IRMOF-10-based carriers exhibit 63.96% drug loading, slow release profiles, and enhanced pro-apoptotic effects in HepG2 cells by elevating ROS and depolarizing mitochondrial membranes [217]. Co-delivery systems combining curcumin with doxorubicin or cisplatin within transformable peptide nanocarriers suppress metastasis and angiogenesis by modulating MMPs and VEGF pathways, validated in vivo through reduced tumor burden and improved histopathology [218].

Clinical and translational advances underscore the viability of these systems. Phase I/II trials of liposomal curcumin (e.g., SinaCurcumin®) in inflammation reveal accelerated symptom resolution and immunomodulatory effects, supporting repurposing for oncology. Ongoing studies explore folate-conjugated and EGFR-targeted LPNs to amplify radiosensitization in prostate and lung cancers [219]. However, challenges persist in scalable manufacturing, long-term toxicity profiling, and regulatory approval of multifunctional nanocarriers.

In summary, curcumin nanomedicines represent a paradigm shift in oncology therapeutics, merging enhanced bioavailability with mechanistically diverse antitumor actions. Future efforts should prioritize combinatorial regimens integrating nanotechnology with conventional therapies to maximize clinical outcomes (Tables 3).

Table 3.

Classification and characteristics of smart nanocarriers for curcumin delivery

Nanocarrier type	Subtypes	Key features	Advantages	Representative applications	Reference
Polymeric nanoparticles	PLGA, chitosan, gelatin	Biodegradable, tunable release kinetics; surface functionalization possible	High encapsulation efficiency (up to 94%); prolonged circulation	Colorectal cancer (chitosan-gum arabic hybrids)	[101]
Lipid-based carriers	Liposomes, NLCs, exosomes	Biocompatible; enhanced lymphatic uptake; biomimetic properties	High bioavailability (11.93-fold vs. free curcumin); low immunogenicity	Triple-negative breast cancer (HA-decorated liposomes)	[108, 178–180]
Inorganic nanoparticles	MSNs, AuNPs	Porous structure (MSNs); photothermal properties (AuNPs)	High loading capacity; stimuli-responsive release	Cervical Cancer (Au-curcumin conjugates	[133]
Stimuli-responsive systems	pH-, redox-, enzyme-sensitive	Triggered release in tumor microenvironment (pH 5.5–6.8; high GSH/MMPs)	Spatiotemporal drug release; minimized off-target toxicity	Pancreatic cancer (MMP-responsive hydrogels)	[151]

Synergistic mechanisms and combination therapies

Chemo-curcumin nano-delivery systems

Synergistic therapy utilizing nanoparticle co-delivery systems represents a pivotal advancement in enhancing curcumin’s anticancer efficacy by leveraging complementary mechanisms with conventional chemotherapeutics. This approach fundamentally addresses multiple limitations of traditional chemotherapy, including multidrug resistance (MDR), systemic toxicity, and inadequate tumor penetration [220]. The strategic co-encapsulation of curcumin with chemotherapeutic agents within nanocarriers creates multifunctional platforms that simultaneously overcome biological barriers while amplifying therapeutic outcomes through pharmacodynamic interactions.

Poly(lactic-co-glycolic acid) (PLGA) nanoparticles have emerged as particularly effective carriers due to their biocompatibility, controlled release properties, and adaptability for surface functionalization [221, 222]. In breast cancer models, doxorubicin-curcumin (CUR-DOX) nanoformulations demonstrate remarkable synergy by concurrently attacking cancer cells through multiple pathways. Specifically, Sarkar et al. reported that this combination treatment significantly induces S-phase cell cycle arrest in Triple-Negative Breast Cancer (TNBC) cells, achieving a 3-fold higher apoptosis rate compared to monotherapy, effectively halting proliferation in this aggressive subtype and demonstrating superior efficacy compared to monotherapies [223].

In the context of breast cancer MDR, recent investigations have elucidated that the synergistic potency of Curcumin and Doxorubicin (DOX) within polymeric nanocarriers (e.g., nanomicelles) extends beyond simple co-delivery [224]. To further refine this synergy, Zeng et al. developed a “Shell-Core” bilayer nanoparticle system as a co-delivery platform. This advanced architecture is engineered to render a synchronized response to the tumor microenvironment, thereby optimizing the spatiotemporal release of both drugs to maximize antitumor effects and overcome resistance [224]. Similarly, a 2023 study [225] demonstrated that nanomicelles co-encapsulating DOX and Curcumin could effectively reverse multidrug resistance in cancer cells by competitively inhibiting the P-glycoprotein (P-gp) efflux pump [226]. The nanoformulation achieved high encapsulation efficiency and facilitated the nuclear accumulation of DOX, which is typically expelled in resistant cells [227]. Furthermore, recent advancements have introduced targeted co-assembly micelles that exhibit synergistic cytotoxicity. These systems not only enhanced the intracellular retention of DOX compared to free drug combinations but also utilized Curcumin to modulate apoptotic signaling pathways, thereby significantly improving anti-tumor efficacy against resistant breast cancer cell lines. Advanced formulations incorporating photoresponsive elements, such as perfluorooctyl bromide (PFOB) in PLGA nanoparticles, enable laser-triggered drug release that further enhances intracellular doxorubicin accumulation by 76–84% [228], significantly suppressing tumor proliferation and migration through reactive oxygen species (ROS) generation and caspase-3 activation. Targeted delivery systems like transferrin-conjugated nanoparticles demonstrate superior biodistribution, with recent evidence showing 40% greater tumor accumulation than non-targeted versions, substantially improving survival outcomes in xenograft models [229].

For pancreatic cancer, the co-delivery of gemcitabine and curcumin (GEM-CUR) in albumin-based nanoparticles addresses the critical challenge of stromal barrier penetration. The 2022 RGD-HSA-GEM/CUR nanoparticle system demonstrates a 200% improvement in drug diffusion through tumor stroma compared to free drug combinations [193]. This enhanced penetration translates to significant in vivo efficacy, with RGD-modified nanoparticles reducing tumor volumes to 354.6 mm³, representing a 55% reduction compared to the free drug group (781.4 mm³) and a 71% reduction compared to the saline control group after 27 days treatment, attributed to curcumin’s ability to downregulate fibrosis-associated proteins and inhibit cancer-associated fibroblasts. The targeted formulation simultaneously suppresses MDR1 and BCL-2 expression at mRNA levels, overcoming inherent chemoresistance while maintaining negligible systemic toxicity as evidenced by stable murine body weights throughout treatment [230].

Beyond direct cytotoxicity, emerging research highlights curcumin’s immunomodulatory synergy with checkpoint inhibitors. Nanodelivery systems enhance curcumin’s bioavailability sufficiently to inhibit STAT3 signaling in dendritic cells, thereby augmenting anti-PD-1 therapy by reducing regulatory T-cell infiltration and restoring CD8 + T-cell functionality [231, 232]. This immunotherapeutic combination demonstrates particular promise in resistant malignancies where conventional immunotherapy fails, though clinical validation remains ongoing. Similarly, innovative photothermal-curcumin hybrid systems like gold-nanorod vesicles enable sequential drug release under near-infrared irradiation, achieving synergistic cell cycle arrest (S-phase) and apoptosis induction unattainable with single-modality approaches [233].

Despite these advances, clinical translation requires optimization of drug loading capacities (currently averaging <10% w/w in polymeric systems), refinement of tumor-specific targeting ligands, and comprehensive toxicological profiling [222]. Future developments should focus on multifunctional “smart” nanoparticles responsive to tumor microenvironmental cues (pH, enzymes, redox gradients) to achieve spatiotemporal control over drug release [234]. The integration of stromal-modulating agents alongside cytotoxic combinations presents a promising frontier for overcoming physical barriers in desmoplastic tumors [230].

Collectively, these nano-enabled combination strategies transform curcumin from a pharmacologically challenged compound into a potent cornerstone of modern cancer therapy regimens. By simultaneously addressing bioavailability limitations, tumor microenvironment barriers, and multidrug resistance while amplifying therapeutic synergy, engineered co-delivery systems significantly expand the clinical potential of curcumin-based anticancer interventions.

Immunotherapy combinations

The integration of curcumin (CUR) with immune checkpoint inhibitors, particularly anti-PD-1 antibodies, represents a cutting-edge strategy in cancer immunotherapy by synergistically remodeling the immunosuppressive tumor microenvironment (TME). Curcumin exerts multifaceted immunomodulatory effects, including inhibition of the STAT3 signaling pathway, which is frequently hyperactivated in tumors and contributes to dendritic cell (DC) dysfunction and T-cell exhaustion. By targeting STAT3, CUR restores DC-mediated antigen presentation and enhances the priming of tumor antigen-specific CD8 + T cells, thereby augmenting the efficacy of PD-1 blockade [231]. In preclinical studies using the 4T1 murine breast cancer model, the combination of CUR and anti-PD-1 therapy significantly increased intratumoral CD8 + T-cell infiltration by 50% while concurrently reducing regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), which collectively dismantle immunosuppressive barriers and potentiate cytotoxic T lymphocyte (CTL) activity [235, 236]. This immunogenic shift is further amplified by CUR’s ability to repolarize tumor-associated macrophages (TAMs) from the pro-tumor M2 phenotype to the antitumor M1 phenotype and to suppress immunosuppressive cytokines like IL-10, TGF-β, and VEGF [237].

Despite its potent immunomodulatory properties, curcumin’s clinical translation has been hindered by poor aqueous solubility, rapid systemic metabolism, and low oral bioavailability (<1%). To overcome these limitations, smart nanoparticle delivery systems have been engineered to enhance CUR’s pharmacokinetics and tumor-targeted delivery. Liposomal formulations, for instance, encapsulate CUR within biocompatible phospholipid bilayers, shielding it from degradation and improving cellular uptake. Moreover, specific protein-based nanocarriers like heavy chain ferritin (HFn) nanocages (Cur@HFn) have demonstrated precise pH-triggered disassembly. These systems exhibit a 3-fold faster drug release rate at endosomal pH (5.0–6.0) compared to physiological pH, and have achieved approximately 50% tumor regression in breast cancer models by ensuring high intracellular drug concentration [238]. Surface modification with polyethylene glycol (PEG) extends circulation half-life, while functionalization with ligands (e.g., glycoproteins or antibodies) enables active targeting to tumor cells or immune cells within the TME [11]. Similarly, polymeric nanoparticles (e.g., PLGA-based carriers) and micellar systems (e.g., Pluronic/PCL copolymers) achieve high drug-loading capacities and sustained release, significantly boosting CUR concentrations in tumor tissues [239]. In the 4T1 model, nanoformulations like Gemini-CUR—a lipid-polymeric hybrid nanoparticle—demonstrated enhanced tumor accumulation and potentiated apoptosis through downregulation of MMP-9, VEGF, and Bcl-2, providing a robust platform for combination immunotherapy [240, 241].

Emerging clinical evidence supports the feasibility of CUR-based nanomedicines in augmenting immunotherapy. A pilot trial combining oral nanocurcumin with pembrolizumab (anti-PD-1) in cervical and uterine cancer patients reported improved therapeutic responses and reduced immunosuppressive factors, suggesting gut microbiota modulation as a potential mechanism [242]. Ongoing clinical trials are evaluating nano-CUR formulations (e.g., liposomal CUR and micellar CUR) across diverse cancers, with several in Phase I/II. However, challenges persist, including batch-to-batch variability in nanocarrier synthesis, long-term biosafety concerns, and the need for optimized dosing regimens in combinatorial protocols [243]. Future directions include developing stimuli-responsive nanocarriers that release CUR in response to TME-specific cues (e.g., pH or enzymes) and hybrid nanoparticles co-delivering CUR with other immunomodulators (e.g., TLR agonists) to further amplify antitumor immunity [244].

In summary, CUR nanoparticle delivery systems not only resolve bioavailability limitations but also strategically reprogram the TME to overcome resistance to PD-1 blockade. As clinical trials advance, these targeted nanoplatforms hold transformative potential for enhancing the precision and efficacy of cancer immunotherapy.

Theranostic applications

The integration of iron oxide-curcumin hybrid nanoparticles represents a transformative advancement in theranostic oncology, leveraging multimodal imaging capabilities to achieve real-time tumor tracking and enhanced therapeutic efficacy. These nanoconstructs, synthesized via green co-precipitation or metal-chelated methods [245], exploit curcumin’s inherent bioactivity while incorporating superparamagnetic iron oxide nanoparticles (SPIONs) for magnetic resonance imaging (MRI) contrast. The resulting hybrids exhibit synergistic functionalities: SPIONs provide high T₂-weighted MRI contrast for anatomical localization [246], while curcumin-derived fluorescence enables cellular-level visualization [247, 248]. In CT26 colorectal carcinoma models, such dual-labeled nanoparticles achieved 60% tumor suppression through mechanisms involving pH-responsive drug release and oxidative stress amplification [249]. This suppression is attributed to curcumin’s modulation of PI3K/AKT/mTOR pathways and iron-mediated Fenton reactions, which collectively induce apoptosis and inhibit metastasis [250].

Recent innovations in surface engineering have further optimized tumor targeting and biocompatibility. Functionalization with polyethylene glycol (PEG) or tumor-homing peptides (e.g., RGD) extends systemic circulation while facilitating active accumulation in neoplastic tissues via enhanced permeability and retention (EPR) effects [251]. A study demonstrated that copper silicate nanoparticles co-loaded with curcumin could deplete intratumoral glutathione and alleviate hypoxia, thereby amplifying photodynamic-chemodynamic synergy and achieving 80% growth inhibition in CT26 models [252]. Such combinatorial approaches address the tumor microenvironment’s immunosuppressive nature, as evidenced by macrophage repolarization toward antitumor M1 phenotypes [253].

Beyond monotherapy, these platforms enable precision-guided synergistic regimens. MRI-fluorescence navigation permits spatially controlled hyperthermia or radiotherapy, where localized heating from alternating magnetic fields triggers curcumin release while sensitizing cancer cells to ionizing radiation [254, 255]. The 2023 DEGRO trial highlighted zinc oxide-curcumin hybrids enhancing radiotherapeutic efficacy through ROS potentiation and DNA damage amplification [256]. Moreover, carrier-free nanodrug assemblies (e.g., curcumin-siRNA conjugates) exploit endogenous biomolecules for self-delivery, bypassing traditional nanocarrier limitations [257].

Crucially, nanoparticle encapsulation overcomes curcumin’s pharmacokinetic barriers: poor aqueous solubility, rapid glucuronidation, and systemic clearance. Lipid-polymer hybrid nanoparticles (e.g., alginate/chitosan-coated SPIONs) enhance oral bioavailability by approximately 20-fold in rodent models via lymphatic uptake and enzymatic degradation shielding [258, 259]. The 2024 glucose oxidase-Fe₃O₄ system exemplifies metabolic modulation, where cascadic ROS generation from glucose depletion and curcumin release induces immunogenic cell death [250]. Future directions include CRISPR-Cas9 co-delivery for gene-editing-enhanced therapy and clinical translation of GMP-compliant nanoformulations [257].

Collectively, iron oxide-curcumin theranostics epitomize next-generation oncology tools, merging diagnosis, targeted delivery, and multimodal treatment within a unified platform. Their efficacy in aggressive models like CT26 colorectal cancer underscores potential clinical relevance, pending large-scale biocompatibility studies and Phase I trials [260].

Clinical translation: from early failures to emerging successes

The clinical translation of smart nanoparticle delivery systems for curcumin has evolved significantly over the past 5 years. While early phase I studies (e.g., the 2018 Lipocurc™ trial) [261] primarily identified dose-limiting toxicities and pharmacokinetic instability [236], recent investigations have shifted focus toward combinatorial regimens and biomarker-driven stratification, revealing more robust efficacy signals.

Safety, pharmacokinetics, and formulation constraints

Recent advancements have successfully addressed the historical challenge of negligible oral bioavailability. A pivotal 2023 crossover study demonstrated that a novel solvent-free co-grinding nanostrategy (CUMINUP60®) achieved a 178-fold increase in plasma Area Under the Curve (AUC) in healthy human volunteers compared to standard crystalline curcumin [79]. Unlike earlier formulations that precipitated rapidly, this strategy utilized water-soluble carriers to maintain supersaturation, significantly extending the absorption window without adverse events. Similarly, comparative pharmacokinetic evaluations in 2024 confirmed that optimized solid lipid nanoparticles (SLNs) and amphiphilic polymer assessments could extend the systemic circulation half-life from minutes to hours, effectively shielding the labile β-diketone moiety from hydrolytic degradation. Regarding safety profile updates, clinical data from nanomicellar formulations have demonstrated superior tolerability compared to the hemolytic risks observed in earlier liposomal infusions [24]. In a randomized trial involving COVID-19 patients (2021), nanomicellar curcumin (Sinacurcumin®) administered at 80 mg/day for 14 days showed no hepato-renal toxicity, with patients exhibiting stable serum creatinine and liver enzyme levels, thereby establishing a safety baseline for sustained oral dosing in inflammatory conditions [262]. However, formulation constraints persist in the realm of long-term biocompatibility. 2023–2024 toxicological reviews highlight that while acute toxicity is manageable, the chronic accumulation of non-biodegradable carriers (e.g., certain metallic or high-molecular-weight polymeric components) in the reticuloendothelial system remains a concern [10]. Furthermore, achieving consistent drug loading remains a bottleneck; recent comparisons indicate that while polymeric micelles offer high stability, they often suffer from low drug loading capacities (<10%), necessitating large carrier volumes to achieve therapeutic doses in oncology, which complicates patient compliance and industrial scalability.

Efficacy endpoints and clinical outcomes

Despite these constraints, preliminary efficacy signals have been observed. In the Lipocurc™ trial, while no objective response rate (ORR) was observed per RECIST v1.1, two heavily pretreated patients (one with prostate carcinoma and another with colon carcinoma) exhibited significant tumor marker reductions and transient clinical benefit, suggesting potential biological activity in select subpopulations. More encouraging efficacy data were derived from combinatorial regimens. Early-phase trials such as the CUFOX IIa and G-NLC + FOLFIRI studies have shown positive outcomes, including improved overall survival (OS) (HR = 0.339) and progression-free survival (PFS) (12.8 months) [172]. Regarding NanoCurc™, although it demonstrates robust preclinical promise by enhancing blood-brain barrier penetration in glioblastoma models [263], its clinical evaluation has often targeted non-oncological endpoints. For instance, ongoing studies (e.g., NCT04853199) prioritize inflammatory biomarkers in breast cancer over antitumor efficacy [264]. Consequently, the clinical translation of curcumin nanoformulations remains at an early stage, with findings derived from small, often non-randomized studies that require validation in larger, controlled trials [265].

Limitations of current clinical evidence

Current clinical findings, while promising, are constrained by inherent limitations in trial design and evidence quality.

Sample size and study design

Most efficacy data are derived from Phase I/II trials with small cohorts (e.g., N = 28 in CUFOX, N = 44 in G-NLC trials). The lack of large-scale, randomized, multicenter Phase III trials limits the statistical power to confirm survival benefits (OS) definitively.

Patient heterogeneity

Early-phase trials often enroll heavily pretreated patients with refractory disease, which may obscure the true efficacy of nanoformulations due to compromised immune systems or multidrug resistance. Future trials require better patient stratification based on biomarkers (e.g., FRα or CD44 expression) to identify responders.

Endpoint interpretation

Many studies rely on surrogate endpoints like Progression-Free Survival (PFS) or tumor marker reduction. While valuable, these do not always translate to long-term Overall Survival (OS) benefits, necessitating longer follow-up periods.

However, resolving these clinical trial limitations is only half the battle. Even if efficacy is proven, the widespread adoption of these nanomedicines is currently bottlenecked by upstream industrial challenges, specifically the difficulty of manufacturing these complex systems at a commercial scale (Table 4).

Table 4.

Selected clinical trials of curcumin nanoformulations in cancer therapy

Trial name/ID	Formulation	Indication	Phase (N)	Key results & clinical outcomes	Ref.
Lipocurc™(NCT02138995)	Liposomal Curcumin	Advanced Solid Tumors	Phase I (N = 32)	Safety: MTD established at 300 mg/m² (6 h infusion). Efficacy: No objective response; stable disease in some patients.	[261]
CUFOX(NCT01490996)	Curcumin C3-Complex	Metastatic Colorectal Cancer	Phase IIa (N = 28)	Survival: Adding curcumin to FOLFOX improved OS (HR 0.34) and PFS. Tolerability: Safe and well-tolerated.	[172]
G-NLC(NCT02439385)	Nanostructured Lipid Carrier	Metastatic Colorectal Cancer	Phase II (N = 44)	Efficacy: Median PFS 12.8 mo; Median OS 30.7 mo. Outcome: Significant improvement in disease control rate (DCR).	[171]
PRIMMO(NCT03192059)	Nanocurcumin (Oral)	Cervical & Endometrial Cancer	Phase II (N = 43)	Outcome: Did not meet primary endpoint for ORR. Observation: Modest immune modulation observed; good safety profile.	[242]

Barriers to translation: the “bench-to-bedside” gap

The clinical translation of smart nanoparticle delivery systems for curcumin faces substantial challenges in scalability and manufacturing, with batch variability and Good Manufacturing Practice (GMP) compliance representing critical hurdles. PLGA nanoparticles (NPs), a widely studied carrier for curcumin, exhibit significant inter-batch heterogeneity in encapsulation efficiency (EE), with reported fluctuations ranging from 21% to 94% [266]. This inconsistency primarily stems from subtle variations in solvent selection, stabilizer concentrations (e.g., PVA, vitamin E-TPGS), emulsification methods (single vs. double emulsion), and even operator technique, as demonstrated by studies showing trained individuals producing NPs with average diameters varying between 220 nm and 364 nm despite identical protocols [267]. Such variability directly impacts critical quality attributes (CQAs) like particle size, polydispersity index (PDI), zeta potential, and drug loading [268], ultimately compromising the reproducibility of pharmacokinetic profiles and therapeutic efficacy in vivo. For instance, ζ-potential measurements across different PLGA NP formulations can range from −31.1 mV to +3.71 mV [269], influencing colloidal stability and biodistribution, while PDI values from 0.192 to 0.542 indicate broad size distributions that affect tumor penetration and clearance rates. Ensuring batch-to-batch consistency necessitates rigorous process control, including meticulous characterization of each batch and strategic pooling strategies to homogenize critical parameters before further modification or administration [270].

The stringent requirements of GMP compliance introduce another layer of complexity and cost to nanoscale manufacturing. Establishing and maintaining the specialized infrastructure, cleanroom facilities, and analytical instrumentation required for reproducible, large-scale production under GMP conditions represents a significant financial barrier, with initial investments potentially reaching $5 million [271]. This high cost is compounded by the inherent complexity of nanomedicine manufacturing, which involves multiple unit operations (emulsification, purification, sterilization, lyophilization) and demands exquisite control over numerous critical process parameters (CPPs) to ensure consistent CQAs [272]. Even minor deviations in parameters like mixing intensity, solvent evaporation rate, or temperature during scale-up can drastically alter NP properties (size, EE, release kinetics) and, consequently, their biological fate and safety profile [273]. Furthermore, sterilization of thermolabile nanocarriers like liposomes or certain polymeric NPs without compromising stability remains a persistent challenge, often requiring expensive aseptic processing techniques instead of terminal heat sterilization [274, 275]. The analytical burden is also heightened, requiring multiple orthogonal characterization techniques (DLS, TEM, HPLC, etc.) for comprehensive batch release testing due to the multifaceted nature of NPs.

Addressing these scalability and manufacturing hurdles requires innovative engineering solutions and advanced process control strategies. Microfluidic technology has emerged as a promising approach to enhance batch consistency. Compared to traditional bulk nanoprecipitation, microfluidic platforms enable superior control over mixing dynamics, shear forces, and supersaturation levels, facilitating the production of NPs with significantly narrower size distributions (PDI < 0.15) and improved reproducibility [276]. For example, optimized microfluidic systems can generate homogeneous PLGA NPs (~150 nm) with high reproducibility, and surface modifications (e.g., with cell-penetrating peptides) can be performed predictably [277]. Scaling microfluidic production is achievable through strategies like parallelization of microchannels, flow rate optimization, and device engineering, with recent reports demonstrating production rates exceeding 1300 mg/h of PLGA NPs [278]. Continuous manufacturing platforms, integrating inline ultrasonication [279] or static mixers [280] with downstream purification like tangential flow filtration (TFF), offer advantages in process control, reduced footprint, and easier scale-up compared to batch processes, aligning better with GMP requirements [272]. TFF, in particular, has proven effective in removing residual solvents and concentrating NPs while maintaining critical attributes like size and PDI [281]. Implementing a Quality by Design (QbD) framework is crucial for robust manufacturing. QbD involves proactively defining the target product profile, identifying CQAs (e.g., size, EE, drug release), understanding the impact of material attributes and CPPs through risk assessment and design of experiments (DoE), and establishing a design space to ensure consistent quality [282]. This systematic approach, applied to processes like wet media milling or high-pressure homogenization, enhances process understanding, reduces batch failures, and facilitates regulatory approval [283].

Finally, exploring novel carrier materials and formulations with inherently improved stability profiles can mitigate manufacturing challenges. Hybrid lipid-polymer nanoparticles and nanostructured lipid carriers (NLCs) offer enhanced stability and drug loading capacities compared to some pure polymeric systems [284]. Advances in stabilizer chemistry, such as optimized PEGylation or alternative stealth coatings, contribute to colloidal stability during manufacturing and storage [285]. Furthermore, optimizing formulations for specific storage conditions (e.g., lyophilization with suitable cryoprotectants for long-term stability) is essential for product shelf-life and distribution logistics [275]. Overcoming the intertwined challenges of batch variability and GMP compliance demands a multidisciplinary approach, combining advanced manufacturing technologies (microfluidics, continuous processing), rigorous quality management systems (QbD), and innovative material science to pave the way for the successful clinical translation of efficacious curcumin nanotherapies.

Regulatory and safety considerations

The clinical translation of smart nanoparticle delivery systems for curcumin faces significant regulatory and safety hurdles, particularly concerning immunogenicity and long-term toxicity, which must be comprehensively addressed to ensure therapeutic efficacy and patient safety. Immunogenicity remains a critical challenge, as polyethylene glycol (PEG)-coated nanoparticles—commonly used to enhance circulation time—can provoke anti-PEG immune responses. Recent studies indicate that approximately 40% of patients develop anti-PEG antibodies after exposure to PEGylated nanocarriers, with pre-existing antibodies detected in 25–44% of healthy individuals due to widespread environmental exposure to PEG in cosmetics, pharmaceuticals, and processed foods [286]. These antibodies, predominantly IgM and IgG, trigger accelerated blood clearance (ABC) of subsequent doses, reduce bioavailability, and may cause hypersensitivity reactions, including anaphylaxis [287]. For instance, mRNA-1273 COVID-19 vaccines boosted anti-PEG IgM by 68.5-fold and IgG by 13.1-fold in clinical trials, correlating with increased hypersensitivity incidents [288]. This immunogenicity compromises curcumin delivery by reducing tumor accumulation and undermining dose-dependent anticancer effects [288, 289].

Long-term toxicity concerns center on nanoparticle accumulation in the mononuclear phagocyte system (MPS), particularly the liver and spleen, where reticuloendothelial clearance leads to persistent retention. Preclinical studies show that intravenously administered curcumin-loaded solid lipid nanoparticles (SLNs) accumulate >50% in the liver and spleen within 24 h, with residual fluorescence detectable for weeks [290, 291]. Such accumulation risks hepatosplenic inflammation, oxidative stress, and granuloma formation, yet chronic toxicity data beyond 6 months remain scarce [292]. This gap stems from methodological limitations: conventional cell cultures cannot sustain long-term exposure assessments, while animal models inadequately predict human immune responses or organ-specific damage [293]. For example, repeated dosing in rats revealed dose-dependent inflammation in hepatic Kupffer cells, but translatability to humans is uncertain due to interspecies variations in MPS activity [294]. Without robust chronic toxicity profiles, regulatory approval is hindered, as agencies like the FDA and EMA require comprehensive biodistribution and safety data extending to at least 12 months for nanomedicines [295].

Regulatory frameworks struggle to standardize safety evaluations, as nanomedicines’ complexity—variable size, surface charge, and degradation kinetics—complicates characterization and risk assessment. The FDA’s 2022 guidance emphasizes rigorous immunotoxicity screening and organ-specific biodistribution studies, while the EMA mandates comparative benefit-risk analyses for nanosimilars [296]. However, neither agency provides definitive protocols for chronic toxicity testing, reflecting broader inconsistencies in global regulations. Japan’s PMDA and India’s 2019 guidelines lack nanomaterial-specific thresholds, and regulatory divergence often classifies similar products as drugs or devices, impeding harmonized safety standards [297, 298]. Novel assessment strategies are emerging, such as adverse outcome pathways (AOPs) integrating in silico modeling and 3D microfluidic organ chips to simulate long-term liver-spleen interactions [299, 300]. Additionally, the REFINE project’s bio-physiokinetic models aim to predict nanoparticle accumulation, though clinical validation is ongoing.

To mitigate these challenges, “safe-by-design” approaches advocate for PEG alternatives, such as poly(glycerol) or zwitterionic polymers, which show reduced immunogenicity in early trials [301]. Concurrently, improved toxicity monitoring via quantitative structure-activity relationship (QSAR) models and multi-omics profiling could address long-term risks [302]. Regulatory alignment through initiatives like the Nanomedicine Characterization Laboratory (NCL) may further standardize requirements, accelerating translation while ensuring safety.

Future perspectives

Emerging technologies

The future of smart nanoparticle delivery systems for curcumin (CUR) hinges on the integration of cutting-edge technologies that synergistically enhance anticancer efficacy and bioavailability. Among the most transformative advancements is the application of artificial intelligence (AI) in nanoparticle design, which transcends traditional empirical approaches. AI-driven algorithms, particularly machine learning (ML) models, analyze vast datasets on polymer-drug interactions, physicochemical properties, and formulation parameters to predict and optimize encapsulation efficiency (EE). For instance, ML techniques such as Support Vector Regression (SVR) and Gaussian Processes have demonstrated the capability to elevate EE in poly(lactic-co-glycolic acid) (PLGA) nanoparticles beyond 90%, a significant improvement over conventional methods that typically achieve ~70% EE [303]. This optimization stems from AI’s ability to identify critical factors like PLGA molecular weight, lactide-to-glycolide ratio, and surfactant concentration, thereby streamlining nanocarrier development while minimizing trial-and-error experimentation [304]. Furthermore, AI facilitates the design of nanocarriers with tailored size, surface charge, and drug-release kinetics, which are crucial for improving tumor targeting and cellular uptake [305]. The integration of AI with microfluidic chip technology further refines nanoparticle fabrication, enabling precise control over parameters such as flow rates and reagent concentrations to enhance batch consistency and scalability.

Concurrently, CRISPR-Cas9 co-delivery systems represent a paradigm shift in precision oncology. Nanoparticles co-loaded with CUR and single-guide RNAs (sgRNAs) can simultaneously deliver chemotherapeutic and gene-editing payloads to disrupt oncogenic pathways. For example, sgRNAs targeting the KRAS oncogene—a driver mutation in >90% of pancreatic ductal adenocarcinomas (PDACs)—can be encapsulated alongside CUR in polymeric or lipid-based nanovehicles [306]. Upon cellular internalization, the CRISPR-Cas9 machinery induces double-stranded breaks in KRAS, silencing its expression and synergizing with CUR’s pro-apoptotic and anti-inflammatory effects [307]. This combinatorial approach not only amplifies tumor cell death but also mitigates drug resistance, as evidenced by studies where peptide-based nanoparticles delivered KRAS-targeting siRNA to desmoplastic pancreatic tumors, suppressing cancer progression in vivo [308]. The precision of this strategy is enhanced by ligand-functionalized nanoparticles (e.g., CCK-B receptor-targeted systems) that navigate the dense tumor microenvironment, ensuring selective delivery to malignant cells while sparing healthy tissues.

Looking ahead, the convergence of AI-optimized nanoparticles and CRISPR-Cas9 co-delivery promises a new frontier in personalized cancer therapy. AI can predict optimal sgRNA sequences to minimize off-target effects and design nanocarriers for co-encapsulating CUR and CRISPR components with high efficiency [309]. Emerging platforms, such as gold nanoparticles or bioreducible lipid nanoparticles, further enhance this synergy by facilitating endosomal escape and intracellular release of Cas9-sgRNA ribonucleoproteins (RNPs) [310]. However, challenges persist, including ensuring the biocompatibility and long-term safety of nanomaterials, addressing potential immune responses to CRISPR components, and validating these systems in large-scale clinical trials [311]. Regulatory frameworks for AI-driven nanomedicine and CRISPR-based therapies also require refinement to accelerate translational applications. Despite these hurdles, the fusion of AI and gene editing within nanodelivery systems heralds a transformative era for CUR-based oncology, offering hope for malignancies with limited treatment options, such as PDAC (Tables 5).

Table 5.

Preclinical efficacy and mechanisms of curcumin nanocarriers in specific cancer models

Cancer type	Nanocarrier formulation	Study design & dose/regimen	Key quantifiable efficacy	Molecular mechanism/targeting strategy	Reference
Colorectal cancer	MPEG-PCL Micelles	In vivo (C26 Xenograft) Dose: 25 mg/kg, IV	50% reduction in tumor volume in C26 murine colon carcinoma xenografts (p < 0.05).	Passive Targeting: High encapsulation efficiency (99%) utilizes EPR effect.	[167]
	HA-grafted PLGA Micelles	In vitro (HCT-116 cells) Conc: 10–50 µM	Significantly higher cytotoxicity in HCT-116 cells compared to non-targeted controls (p < 0.05).	Active Targeting: CD44-mediated endocytosis exploits receptor overexpression.	[161]
Breast cancer (TNBC)	HA-decorated Liposomes	In vivo (Lung Metastasis) Route: IV administration	70% suppression of pulmonary metastasis in 4T1 tumor-bearing mice (p < 0.01).	Anti-Metastasis: Inhibition of CSC self-renewal and CD44 receptor binding.	[181]
	HA-decorated Liposomes	In vivo (MDA-MB-231) Route: IV administration	3.3-fold higher tumor drug accumulation vs. free drug (p < 0.05).	Biodistribution: Enhanced permeability and retention (EPR) plus active targeting.	[178–180]
Breast cancer	CUR-DOX PLGA NPs	In vivo (MDA-MB-231) Conc: ~20 µg/mL (Combined)	3-fold higher apoptosis rate vs. monotherapy in MCF-7 cells (p < 0.05).	Synergy: Reversal of MDR via NF-κB/P-gp inhibition.	[223]
Pancreatic cancer	Gemcitabine-Curcumin NPs	In vivo (Orthotopic)Regimen: Co-delivery	71% reduction in tumor volume in orthotopic models (p < 0.01).	Stromal Modulation: Disruption of hyaluronan/collagen barriers.	[193]
	NanoCurc™ (Polymeric)	In vivo (Pan02 Xenograft) Dose: 25 mg/kg, IP daily	Extended median survival from 28 to 63 days in xenograft models (p < 0.001).	Immunomodulation: Enhanced bioavailability; Reduced oxidative stress.	[190, 191]
Glioblastoma	Transferrin-conjugated NPs	In vivo (BBB Model) Route: IV administration	Up to an 8-fold increase in brain curcumin concentration (p < 0.05).	BBB Crossing: TfR-mediated transcytosis.	[206, 207]
	Transferrin-conjugated NPs	In vivo (U87MG Xenograft) Route: IV administration	45% reduction in tumor growth compared to free curcumin (p < 0.05).	Signaling Inhibition: Disruption of AKT/mTOR signaling; Induction of apoptosis.	[206, 207]
Lung cancer	Curcumin-loaded SLNs	In vitro (A549 cells) Conc: 5–40 µM	60–75% apoptosis in A549 cells observed in vitro (p < 0.001).	Cellular Uptake: Enhanced uptake and sustained release profile.	[210]
Prostate cancer	NLCs (Nanostructured Lipid Carriers)	In vivo (Xenograft) Route: Intratumoral/IV	Reduced tumor volume by 40% through enhanced cellular uptake.	Apoptosis Induction: Sustained release and enhanced cellular uptake.	[111]

Personalized nanomedicine

The future of personalized nanomedicine in curcumin delivery represents a paradigm shift toward precision oncology, where genomic profiling serves as the cornerstone for ligand selection in nanoparticle design. By analyzing tumor-specific receptor expression patterns through multi-omics approaches (e.g., transcriptomics, proteomics), clinicians can identify optimal targeting ligands—such as folate for FRα-overexpressing tumors or transferrin for TfR-dominant malignancies—thereby maximizing tumor-specific uptake while minimizing off-target effects [312]. For instance, FRα is overexpressed in >80% of ovarian carcinomas and 30–50% of non-small cell lung cancers, whereas TfR shows significant upregulation in glioblastoma and metastatic tumors [313, 314]. This biomarker-driven strategy leverages advanced ligand screening technologies, including phage display and SELEX, to identify high-affinity aptamers or peptides that bind cognate receptors with nanomolar specificity [315].

Recent clinical advances underscore the translational potential of this approach. Phase I/II trials of biomarker-stratified nanotherapeutics—such as folate-targeted liposomal doxorubicin in FRα+ solid tumors and TfR-directed nanoparticles for glioblastoma—demonstrate enhanced therapeutic indices and reduced systemic toxicity compared to untargeted systems [316]. Notably, the INFORM2 NivEnt trial exemplifies how molecular profiling (e.g., WES, RNA-seq) guides patient stratification for targeted nanotherapy, achieving objective responses in 85% of biomarker-selected cohorts [317]. For curcumin specifically, genomic analysis of tumor redox environments (e.g., Nrf2/KEAP1 mutations) could inform the design of stimuli-responsive nanocarriers that release curcumin upon encountering tumor-specific oxidative stress, thereby exploiting molecular heterogeneity to boost anticancer efficacy.

Artificial intelligence further revolutionizes ligand-receptor matching through deep learning models that predict binding affinities and tumor homing efficiency. Multi-omics integration algorithms—trained on TCGA data and patient-derived organoids—can simulate curcumin pharmacokinetics in virtual patient cohorts, identifying optimal ligand-receptor pairs (e.g., folate vs. transferrin) based on individual tumor receptor stoichiometry [318]. For example, Hass et al. demonstrated that AI-driven models incorporating receptor dimerization patterns predicted ligand-dependent proliferation with 92% accuracy across breast and colorectal cancers [319]. Such computational frameworks, when coupled with real-time biosensor feedback from theranostic nanoparticles, could dynamically adjust ligand density or composition during treatment [320, 321], creating adaptive “smart” systems that evolve with the tumor’s molecular landscape.

Despite these advances, clinical implementation faces hurdles. Tumor receptor heterogeneity necessitates multi-ligand nanoparticles capable of targeting co-expressed biomarkers (e.g., FRα + EGFR), while endosomal escape barriers limit cytoplasmic curcumin delivery even after receptor-mediated uptake [322, 323]. Emerging solutions include “AND-gate” nanoparticles responsive to dual biomarkers and endosomolytic polymers that disrupt endosomal membranes upon pH activation. Moreover, scalable manufacturing of patient-specific nanocarriers requires standardized quality control protocols for ligand conjugation efficiency and batch-to-batch reproducibility—challenges being addressed through microfluidic production platforms. As biomarker validation trials (e.g., NANO-GBM) mature, the convergence of genomic profiling, AI-driven design, and modular nanocarrier systems promises to transform curcumin from a pleiotropic natural compound into a precision weapon against molecularly defined cancers [324, 325].

Sustainability and cost-effectiveness

The pursuit of sustainable and cost-effective strategies is paramount for the clinical translation of curcumin-loaded nanoparticle delivery systems. Plant-derived exosomes (PDEs), particularly those sourced from turmeric, represent a revolutionary approach to minimizing production costs while leveraging biocompatible nanocarriers. PDEs are natural extracellular vesicles that circumvent the need for complex synthetic processes, utilizing inherent biological machinery for nanoparticle formation [326]. Recent studies indicate that turmeric exosomes can reduce synthesis costs by approximately 70% compared to conventional liposomal or polymeric nanoparticles, primarily by eliminating expensive raw materials and energy-intensive manufacturing steps [327]. Beyond economic advantages, PDEs enhance drug stability and targeting specificity. Their lipid-protein architecture facilitates membrane fusion with cancer cells, improving curcumin’s intracellular delivery while reducing off-target toxicity [328]. However, challenges persist in standardizing isolation methods (e.g., ultracentrifugation, immunoaffinity) and scaling production without compromising vesicle integrity [329].

Complementary to PDEs, solvent-free green synthesis methods have emerged as a cornerstone for sustainable curcumin encapsulation. These approaches minimize environmental hazards by avoiding toxic organic solvents, instead employing mechanisms like anti-solvent precipitation or mechanochemical reactions to form curcumin-loaded PLGA nanoparticles (CUR-PLGA NPs) [330]. Recent optimizations have achieved encapsulation efficiencies (EE) exceeding 88%, attributed to precise control over polymer-drug interactions during nanoparticle self-assembly [331]. The absence of solvents not only reduces waste but also enhances process safety and scalability. For instance, boron-assisted imine formation in solvent-free systems enables high-yield curcuminoid synthesis with minimal purification steps, underscoring the method’s industrial viability [332]. Moreover, green-synthesized CUR-PLGA NPs demonstrate superior bioavailability; their sustained release profiles in intestinal environments enhance curcumin absorption by 5.6-fold compared to free curcumin, while PLGA’s biodegradability ensures systemic clearance without residual toxicity [333].

The environmental and economic benefits of these strategies are quantifiable through life-cycle assessments (LCAs). Solvent-free synthesis reduces energy consumption by 40–60% and cuts aquatic ecotoxicity impacts by 2–3 orders of magnitude relative to solvent-based methods [334]. For PDE production, economies of scale further diminish costs, as large-scale exosome harvesting leverages agricultural byproducts (e.g., turmeric waste), aligning with circular economy principles [335, 336]. Nevertheless, regulatory hurdles and standardization gaps—such as undefined quality controls for PDE cargo or PLGA degradation kinetics—require resolution to ensure commercial feasibility. Future frameworks must integrate Safe-by-Design (SbD) paradigms, combining risk assessment with sustainability metrics like process mass intensity (PMI) to holistically optimize nanoparticle production [337, 338].

In conclusion, the synergy between plant-derived exosomes and solvent-free green synthesis heralds a transformative era in curcumin delivery. By prioritizing renewable resources, waste reduction, and cost efficiency, these approaches address the dual imperatives of therapeutic efficacy and environmental stewardship, accelerating the transition from laboratory innovation to clinical reality.

Conclusion

This comprehensive review underscores the transformative potential of smart nanoparticle delivery systems in overcoming the intrinsic limitations of curcumin—a naturally derived polyphenol with compelling multimodal anticancer activity. Encapsulation within advanced nanocarriers (e.g., PLGA nanoparticles, nanostructured lipid carriers, liposomes, mesoporous silica, and biomimetic exosomes) dramatically enhances curcumin’s aqueous solubility, shields it from rapid degradation and metabolism, and extends systemic circulation. These modifications collectively elevate bioavailability to therapeutically relevant levels—achieving up to a 178-fold increase in plasma AUC in humans with specific co-grinding formulations compared to unformulated curcumin—while facilitating passive tumor accumulation via the EPR effect. Critically, “smart” designs incorporating stimuli-responsive elements (pH-, redox-, or enzyme-triggered release) and active targeting ligands (e.g., folate, transferrin, hyaluronic acid, RGD peptides) enable spatiotemporal control over drug release, significantly improving tumor-specific uptake and minimizing off-target toxicity.

The therapeutic efficacy of nanoformulated curcumin extends across diverse, treatment-resistant malignancies. In triple-negative breast cancer, hyaluronic acid-decorated liposomes suppress metastasis by 70% through dual targeting of bulk tumor cells and CD44+ cancer stem cells. For pancreatic ductal adenocarcinoma, gemcitabine-curcumin co-loaded nanoparticles overcome stromal barriers and chemoresistance, achieving 71% tumor reduction in preclinical models. Transferrin-conjugated systems enhance blood-brain barrier penetration in glioblastoma, elevating brain curcumin concentrations 8-fold and suppressing tumor growth by 45%. Furthermore, nano-curcumin potently reverses multidrug resistance by inhibiting P-gp efflux and downregulating survival pathways (e.g., NF-κB, STAT3), while synergizing with conventional chemo/radiotherapy to sensitize resistant cells.

Despite promising preclinical outcomes, clinical translation faces significant hurdles. Heterogeneity in the EPR effect across human tumors necessitates patient stratification strategies. Challenges in scalable, GMP-compliant manufacturing—particularly batch-to-batch variability in encapsulation efficiency (21–94% for PLGA NPs)—and long-term biocompatibility assessments (e.g., hepatosplenic accumulation, PEG immunogenicity) remain unresolved. Early-phase trials of liposomal (Lipocurc™) and polymeric (NanoCurc™) curcumin demonstrate target engagement and biological activity but underscore persistent bioavailability challenges and dose-limiting toxicities (e.g., hemolysis at 300 mg/m²). Future efforts must prioritize multifunctional “theranostic” platforms integrating real-time imaging, AI-optimized ligand selection based on tumor receptor profiling, and CRISPR-Cas9 co-delivery for gene-editing-enhanced therapy. Sustainable strategies, such as plant-derived exosomes and solvent-free synthesis, offer scalable, cost-effective alternatives.

In conclusion, smart nanodelivery systems have revolutionized curcumin from a pharmacologically challenged compound into a precision oncology agent. By harmonizing enhanced pharmacokinetics, tumor-targeted delivery, and microenvironment modulation, these innovations unlock curcumin’s full potential to suppress tumor growth, metastasis, and chemoresistance. Overcoming translational barriers through interdisciplinary collaboration and advanced manufacturing will be pivotal in harnessing this promise for clinical oncology.

Author contributions

Yang Fu and Yuanxin Ge conceived of the presented idea. Yang Fu wrote the manuscript with support from Yuanxin Ge. Shixiong Yi and Qifeng Peng supervised the findings of this work. Heng Jiang analyzed the data. Both Yang Fu and Jie Zhou, authors, contributed to the final version of the manuscript. All authors discussed the results and contributed to the final manuscript.

Funding

This work was supported by Chongqing Traditional Chinese Medicine scientific research project (Joint project of Chongqing Health Commission and Science and Technology Bureau) (No. 2024ZYZD006), The Science and Technology Research Program of Chongqing Municipal Education Commission (Grant No. KJQN202215120), Natural Science Foundation of Chongqing, China (No. cstc2021jcyj-msxmX0853).

Compliance with ethical standards

Conflict of interest

The authors declare no competing interests.