Emerging nanocarriers designed for the enhanced delivery of doxorubicin

ABSTRACT

Doxorubicin(DOX), which is a first-line broad-spectrum chemotherapeutic agent remains constrained clinical efficacy by dose-dependent cardiotoxicity, multidrug resistance, and systemic toxicity. Recent advancements in nanocarrier-based drug delivery systems have demonstrated remarkable potential to enhance tumor-specific accumulation, modulate drug release kinetics, and mitigate off-target effects through innovative engineering strategies. Contemporary nanocarrier researchers have expanded beyond conventional efforts to enhance tumor targeting and optimize drug release kinetics, which emphasizes the pathophysiological roles of the tumor microenvironment (TME) in mediating oncogenesis, neoplastic progression, and therapeutic resistance. This review emphasizes two pivotal strategies: (1) Structural innovation in tumor-targeting nanocarrier design through stimuli-responsive release mechanisms and molecular recognition targeting; (2) Therapeutic reprogramming of the TME via combinatorial extracellular matrix modulation. Through systematic analysis of 2019–2022 literatures from major scientific databases, this review synthesizes the advances in DOX-loaded nanocarriers targeting TME reprogramming and immunomodulation, and evaluates novel delivery platforms that overcome DOX’s dose-limiting toxicity while potentiating antitumor efficacy.

1. Introduction

Doxorubicin (DOX), a broad-spectrum anthracycline antibiotic, has maintained a critical role in cancer chemotherapy since its discovery in 1967, owing to its potent antitumor activity [1]. Initially isolated from Streptomyces peucetius fermentation products, its chemical structure comprises a tetracyclic anthraquinone core conjugated to a daunosamine moiety through glycosidic bonds [2,3]. This unique architecture confers multimodal biological activity, allowing DOX to target multiple pathways in tumor cells and disrupt their growth and proliferation mechanisms.

DOX exhibits broad-spectrum antitumor activity with demonstrated efficacy against various solid tumors and hematological malignancies, including breast cancer, lung cancer, gastric cancer, ovarian cancer, and lymphoma [4–9]. However, the clinical application of this drug has long been limited by two core issues: the first is dose-dependent cardiotoxicity, caused by free radical-mediated myocardial mitochondrial damage that may progress to irreversible heart failure; the second involves systemic adverse reactions such as bone marrow suppression and gastrointestinal toxicity due to nonspecific biodistribution, which necessitates strict limitations on treatment duration and dosage in clinical practice [10,11]. More seriously, tumor cells activate the multidrug resistance (MDR) mechanism by up-regulating effector pump proteins such as P-glycoprotein (P-gp), significantly weakening the therapeutic sensitivity of DOX and forming an efficacy bottleneck [12–14].

In response to these challenges, nano-delivery systems provide breakthrough solutions for DOX precision therapy. Nanotechnology-based delivery carriers leverage size optimization (10-200 nm) to exploit the enhanced permeability and retention (EPR) effect for passive targeting [15], while surface ligand modifications (e.g., folate or RGD peptides) enable active recognition of tumor cell surface receptors [16,17]. The dual mechanism significantly enhances the accumulation efficiency of drugs at the lesion site. For example, 7pep-modified PHIS-PEG₂₀₀₀ and DSPE-PEG₂₀₀₀ mixed micelles loaded with DOX exhibits enhanced targeting capability toward MDR tumors, effectively inhibiting the growth of tumors and lymph node metastases in breast cancer [18]. Additionally, stimuli-responsive nanocarriers enable precise drug release triggered by tumor microenvironmental cues (e.g., pH gradients, hypoxia, or immunosuppression). Representative examples include liposomes, polymeric micelles, metal-organic frameworks (MOFs), albumin nanocarriers, biomimetic nanocarriers and inorganic nanoparticles [19–29] (Figure 1). These sophisticated delivery platforms not only decrease DOX degradation but also mitigate off-target toxicity, thereby improving the compound’s biosafety profile while enhancing therapeutic outcomes in oncology applications.

Figure 1.

Emerging nanocarriers of DOX and the features of TME.

In summary, DOX exerts its anti-tumor effects through multiple mechanisms, including DNA intercalation, topoisomerase II inhibition, oxidative stress induction, and disruption of cellular signaling pathways. These processes are interconnected and functionally synergistic, leading to the suppression of tumor cell growth and proliferation.

2. Nanocarrier-mediated targeted delivery of DOX

DOX demonstrates broad-spectrum antitumor activity. However, when administered in its free form, the drug lacks tumor-targeting specificity. While effectively killing cancer cells, it concurrently damages healthy tissues. To address this limitation, nanocarrier systems designed for tumor-targeted DOX delivery have gained significant research attention. Representative examples include liposomes, polymeric micelles, MOFs, albumin nanoparticles, biomimetic nanocarriers and inorganic nanoparticles (Figure 2) [19–29]. Each carrier system possesses distinct physicochemical characteristics that facilitate targeted drug accumulation at tumor sites (Table 1). These sophisticated delivery platforms not only decrease DOX degradation but also mitigate off-target toxicity, thereby improving the compound’s biosafety profile while enhancing therapeutic outcomes in oncology applications.

Figure 2.

DOX-loaded nanoparticles for efficient cancer therapy.

Table 1.

Novel delivery systems for DOX.

Type	Composition	Treatable disease	Ref.
Liposomes	Peptidomimetic ligand; SS31, a small peptide	HER2 positive lung and breast cancer; glioma	[30,31]
Polymer micelles	Polyethylene glycol -coated liposomes; Succinic anhydride activated pluronic F68	human blood cancer; lung cancer	[20,32]
MOFs	NiCu-MOF; hollow porphyrinic MOFs	Breast cancer; myocardial injury and cardiac dysfunction	[24,33]
Bionic nanocarriers	Polyethylene glycol-coated liposomes; exosomes from neutrophils with SPIONs	Osteosarcoma; gastric cancer	[20,34]
Albumin nanoparticles	Human serum albumin; bovine serum albumin	Liver cancer; breast cancer	[26,35,36]
Inorganic nanoparticles	AuNPs; MSNs; IONPs	Breast cancer; bladder cancer; brain tumor	[37–40]

2.1. Liposomes

Liposomes, comprising a phospholipid bilayer, structurally mimic biological membranes. These nanostructures exhibit excellent biocompatibility, reduce immunogenic reactions, enhance drug stability in vivo, and minimize systemic toxicity. Clinical studies have shown that 4 hours and 24 hours after administration, intratumoral drug delivery in the body increases fivefold, while simultaneously reducing the amount of drug reaching the heart at the equivalent time point by 3 to 5 times [41]. Consequently, liposome-mediated delivery systems enable active tumor targeting through surface-engineered ligands or antibody conjugates [20,42].

Liposomal nanocarriers have emerged as transformative platforms in oncological drug delivery, demonstrating unique advantages in modulating the pharmacokinetic behavior of chemotherapeutic agents. These amphiphilic vesicles prolong systemic circulation through EPR effects while providing sustained release kinetics for payloads such as DOX. Kim et al. reported that nanoscale liposome formulations maintained stability under in vivo conditions, but a decrease in pH progressively enhanced drug release. While the free DOX group failed to achieve significant tumor volume reduction compared to the normal saline control, the optimized liposome formulation demonstrated potent efficacy. Specifically, it significantly inhibited tumor growth, resulting in an approximately 71.7% reduction in tumor volume on the 24^th day [43]. Contemporary research has pioneered stimuli-responsive architectures, particularly pH-sensitive formulations engineered with tumor microenvironment (TME)-cleavable bonds. The developed technology achieves spatiotemporally controlled drug release through pH-responsive mechanisms that exploit the acidic extracellular matrix of tumor tissues. Pioneering studies [30] have engineered pH-responsive liposomal platforms to deliver DOX-mimetic peptide conjugates, enabling targeted drug release in response to the acidic TME. Subsequent analyses demonstrated that liposome-encapsulated conjugates significantly improve biocompatibility while reducing off-target cytotoxicity in nonmalignant cells. For instance, Cen [31] developed a DOX-loaded liposome targeting glioma, which also demonstrated a high drug loading (87.97%) and encapsulation rate (5.50%), as well as good in vitro stability. These formulations demonstrate enhanced biosafety profiles and reduced systemic toxicity compared to free DOX.

Liposomes’ structural similarity to biological membranes confers inherent biocompatibility, while their sustained-release properties enhance DOX bioavailability in vivo and optimize therapeutic efficacy. Engineered structural modifications enable site-specific drug delivery, with targeted DOX release representing a pivotal advancement in nanocarrier design. This approach minimizes off-target effects through ligand-mediated tumor homing mechanisms, exemplifying a strategic paradigm in precision oncology therapeutics. Comparative toxicological assessments consistently reveal superior biosafety profiles of nanoformulated DOX versus conventional administration, with marked reductions in cardiotoxicity and myelosuppression [44,45]. Current developmental trajectories focus on multifunctional “smart” systems integrating real-time imaging capabilities with combination therapy regimens. Nevertheless, challenges persist in industrial-scale manufacturing reproducibility and precise in vivo targeting fidelity, necessitating interdisciplinary collaboration between material scientists and clinical oncologists to bridge translational gaps.

2.2. Polymer micelles

Polymer micelles are nanoscale colloidal systems formed through the self-assembly of amphiphilic polymers in aqueous solutions. These macromolecules contain distinct hydrophilic and hydrophobic blocks, enabling spontaneous organization into core-shell architectures via hydrophobic interactions in a polar domains and hydrogen bonding in polar regions [46]. The hydrophobic core serves as a reservoir for lipophilic drug encapsulation, while the hydrophilic corona stabilizes the micelles through hydration effects, maintaining colloidal stability in physiological environments.

Bayram [22] developed polymer-micelle-encapsulated DOX (PM-DOX) and systematically characterized its physicochemical properties. Aqueous stability was evaluated through NMR spectroscopy and dynamic light scattering, while biocompatibility was validated via in vitro cytotoxicity assays and in vivo murine models. Notably, DOX-NCs exhibited an IC₅₀ of 1.07 × 10⁻⁶ M, whereas DOX-HER2-NCs showed 0.45 × 10⁻⁶ M, demonstrating at least twice the potency of DOX-HER2-NCs over DOX-NCs against cancer cells. These findings position polymeric micelles as advanced nanoplatforms for tumor-targeted DOX delivery, with enhanced therapeutic indices observed in preclinical evaluations. Meanwhile, Zhao [32] developed a stimuli-responsive drug delivery system through covalent conjugation of DOX to Pluronic® F68 copolymers using amide bond formation. Our team [47] developed hyaluronic acid-ferrocene-based micellar systems loaded with DOX (DOX/FCH), which enhance tumor-targeted drug delivery and exhibit synergistic effects with chemo-radiotherapy. The literature describes DOX-loaded nanostructures assembled from diverse molecular components, which exhibit dual functionalities: inherent tumor-targeting capacity and TME-responsive drug release. These systems maintain structural stability under physiological conditions but undergo stimuli-triggered disassembly specifically in tumor tissues, enabling spatiotemporally controlled drug delivery.

The engineered micellar system capitalizes on its amphiphilic architecture to encapsulate DOX via hydrophobic core sequestration, while the hydrophilic corona facilitates prolonged blood circulation through steric stabilization. This structural configuration synergizes with EPR effect to promote preferential drug accumulation at tumor sites. Importantly, the TME-triggered release mechanism ensures precise payload delivery, simultaneously addressing two critical challenges in conventional chemotherapy: systemic toxicity mitigation and therapeutic efficacy potentiation. Further development of these multifunctional nanohybrid micelles demonstrates the convergence of passive and active targeting strategies. The self-assembled core-shell morphology not only improves drug solubility and stability but also enables responsive payload release through tumor-specific stimuli. This integrated approach effectively enhances the therapeutic index by optimizing drug biodistribution profiles while maintaining biocompatibility [48].

2.3. Metal-organic framework nanocarriers

MOFs represent a class of crystalline hybrid materials constructed through coordination-driven self-assembly of metal clusters and organic linkers, forming three-dimensional nanoporous architectures [49,50]. These materials exhibit exceptional surface area, tunable porosity, and programmable chemical functionality, rendering them promising nanocarriers for antitumor drug delivery [51]. The inherent structural characteristics of MOF, including their high specific surface area and modular pore geometries, enable efficient drug encapsulation while maintaining colloidal stability.

Recent advances highlight the translational potential of MOF-based systems in oncology. Sun et al. [33] engineered a biomimetic MOF platform by coating 4T1 breast cancer cell membranes onto porphyrin-based MOF co-loaded with DOX and indocyanine green. This design leverages homologous targeting to enhance tumor accumulation while integrating photodynamic therapy with controlled drug release. Comparative studies demonstrates superior antitumor efficacy of the MOF formulation over conventional chemotherapy regimens. Parallel developments by Liu et al. [24] have addressed DOX-induced cardiotoxicity through bimetallic NiCu-MOFs exhibiting antioxidant and ferroptosis-inhibitory properties. The engineered nanocarriers significantly mitigate cardiomyocyte damage by scavenging reactive oxygen species (ROS) and modulating cell death pathways. Meanwhile, a bimetallic MOF on which the ovalbumin protein loaded and DOX could be released in response at the tumor site. The metal ion Cu in the carrier plays a catalytic role to produce ROS to kill tumor cells. Another metal ion Ca also enables calcium overload therapy in TME. Meanwhile, the loaded OVA protein and DOX are transported to the tumor site and act together on tumor cells, significantly improving the anti-tumor efficacy.

The structural versatility of MOF facilitates multifunctional integration through surface modification strategies. Their three-dimensional porous networks not only achieve high drug-loading capacity but also provide dynamic coordination sites for functional group conjugation [22,52]. This “structure-function” programmability enables spatiotemporal control over drug release kinetics and theranostic integration, positioning MOF as next-generation platforms for precision oncology [53].

2.4. Bionic nanocarriers

Bio-inspired nanocarriers simulate natural biological structures and functions through bionics principles to construct intelligent drug delivery systems. Current mainstream strategies include red blood cell (RBC) membrane coating, tumor cell membrane coating, and exosome engineering. Among them, Cluster of differentiation-47 (CD47) protein on red blood cell membranes enables macrophage escape by binding the SIRPα receptor, significantly prolonging circulation time [54]. RBC membrane coating technology mitigates DOX’s cardiotoxicity and extends systemic circulation by conferring natural cell “invisibility,” while functionalized biomembranes expand immunomodulatory capabilities – establishing this platform as a benchmark for next-generation intelligent drug delivery. Tumor cell membrane modification utilizes transmembrane proteins to mediate homologous targeting, enhancing tumor accumulation efficiency. DOX, and indocyanine green (ICG) to mimic tumor cell migration/invasion characteristics for targeted delivery. A representative system is K562 cancer cell membrane-coated SPIO@DOX-ICG nanoparticles (IDINPs). IDINPs demonstrate multimodal therapeutic potential through the synergistic effects of chemotherapy (DOX release), hyperthermia (ICG photothermal conversion), and radiotherapy [21]. Exosome vectors show unique advantages in addressing DOX-induced cardiotoxicity. Researchers have used human induced pluripotent stem cell-derived mesenchymal stem cell (iPSC-MSC) exosomes as carriers to constructed bifunctional systems by encapsulating DOX/dinindolylmethane (DIM) with silica nanoparticles or modified SPIONs. For example, magnetic-targeted natural exosomes (N-Ex) and ELNV-DOX vectors prepared by extrusion achieved precise magnetically-guided delivery via SPION modification while retaining natural exosomes’ low immunogenicity and ability to cross biological barriers. Notably, breakthroughs in exosome large-scale production have been achieved. Exosome engineering utilizes natural vesicle structures as carriers, significantly extending their in vivo circulation half-life through inherent low immunogenicity and biocompatibility [34].

By emulating biological interface functionalities, these biomimetic strategies synergistically enhance critical performance metrics of drug delivery systems, including prolonged systemic circulation, improved tissue penetration depth, and lesion-specific targeting precision.

2.5. Albumin nanoparticles

Albumin nanoparticles, with advantages of high biocompatibility, non-immunogenicity, and wide availability, have shown great potential in drug conjugation. Modified albumin nanoparticles can be used to encapsulate chemotherapy drugs, enabling targeted drug delivery and release, and reducing side effects on the body [35]. For instance, Yang et al. combined DOX with fatty acids to form a prodrug and utilized albumin nanoparticles for loading and transportation, allowing DOX to be released specifically in TME [26]. Compared with the control group, the drug formulation group avoids the occurrence of hand-foot syndrome in mice. For the treatment of liver cancer, DOX and 5-FU are loaded into mesoporous silica nanoparticles (MSNs) and subsequently encapsulate of approximately 59.71% [36]. Furthermore, based on albumin nanoparticles, precise diagnosis and therapy for tumors can also be achieved. An et al. have prepared a hyaluronic acid and human serum albumin nanocarrier to encapsulate MIL-100(Fe) MOFs, DOX, and radioactive nuclides, which could precisely diagnose and target tumor cells. When the DOX concentration reached 5 μg/mL, the survival rate of 3T3 cells and 4T1 cells were 66.58 ± 1.74% and 52.98 ± 0.96%, respectively [55].

However, the practical application of albumin nanoparticle carriers still faces challenges. The current technical bottleneck mainly lies in the contradiction between drug loading efficiency and targeting accuracy: increasing the drug load often requires enlarging the particle size or introducing auxiliary carriers, which may weaken the carrier’s ability to penetrate the vascular barrier [36]. Solutions include developing sub-100 nm core-shell structures or using multi-point conjugation techniques [56]. Additionally, batch-to-batch uniformity control (PDI <0.15) in large-scale production and the impact of sterilization processes on protein conformation still need in-depth research [57]. Microfluidic continuous production combined with cryoprotectants may be a breakthrough direction.

2.6. Inorganic nanoparticles

2.6.1. Gold nanoparticles

Gold nanoparticles (AuNPs) possess excellent physicochemical stability, dimensional uniformity, and photothermal response characteristics. Moreover, their surfaces are easy to modify with various targeted molecules. By modifying specific ligands onto the surface, targeted delivery to diseased tissues or cells can be achieved [37]. Therefore, gold nanoparticles have become important carrier materials in anti-tumor drug delivery systems [27,38]. To address the systemic toxicity and insufficient drug concentration at tumor sites caused by the difficulty of precisely delivering DOX through traditional nonspecific carriers, researchers have developed an intelligent controlled-release system based on AuNPs: By co-loading DOX on gold half-shell nanoparticles with surface-modified HER2-targeting ligands under near-infrared (NIR) irradiation, the local surface plasmon resonance effect generated by the gold half-shell nanoparticles can efficiently convert light energy into heat energy, achieving localized heating of TME. This triggers the phase transition of the carrier structure and accelerates DOX release. The strategy demonstrates superior efficacy in breast cancer model experiments – photothermal combined chemotherapy reduces tumor volume by 75% within 10 days. Meanwhile, the surface-targeted modification and size effect (20–50 nm) of the nanocarriers significantly reduces DOX accumulation in normal organs such as the heart and kidneys (60–80% lower than free drugs), while achieves complete metabolic clearance within 42 days [58]. More importantly, the monodisperse nature of gold nanoparticles provides an ideal platform for their functionalization: Programmable functionalization (e.g., PEGylation to prolong circulation half-life) [59], multi-drug co-loading (e.g., with photosensitizers or immune checkpoint inhibitors) [27,38], and stimulus-responsive group coupling (pH/GSH-sensitive bonds) collectively construct a spatiotemporally controlled drug release system [60]. This enables DOX to penetrate tumor biological barriers (e.g., dense matrices and high interstitial pressure) while maintaining therapeutic activity, offering an innovative solution for improving chemotherapeutic efficacy indices [61].

2.6.2. Mesoporous silica nanoparticles

Mesoporous silica nanoparticle (MSNs)have become ideal carriers for targeted and controlled drug delivery due to their excellent biocompatibility, tunable structural properties, and high drug-loading capacity. By precisely regulating synthesis conditions, the particle size, pore dimensions, and surface chemistry of MSNs can be customized to achieve efficient encapsulation and controlled release of diverse therapeutic agents (e.g., the chemotherapeutic DOX). However, unmodified MSNs may cause off-target effects and hemolysis risks due to nonspecific interactions between surface silanol groups and cell membranes, limiting their clinical translation. To address this problem, researchers have developed mannose-grafted poly(acrylic acid) copolymer-coated DOX-loaded MSNs (DOX@MSNs-Man-g-PAA). This modification significantly improves nanoparticle hemocompatibility while enhancing tumor-targeting efficiency through mannose receptor-mediated endocytosis [28]. In brain tumor models, these ligand-modified DOX-loaded MSNs increase survival rates by > 28% compared to free DOX, and enhance drug accumulation in brain tissue (6-fold higher), demonstrating their potential for blood-brain barrier penetration and therapeutic enhancement [39]. Furthermore, topological engineering enables fabrication of three-dimensional chiral helical MSN nanorods. This unique morphology enhances bioadhesion, mucus penetration, and cellular uptake efficiency – providing novel strategies for optimizing DOX delivery systems.

In conclusion, MSNs enhance DOX efficacy through a synergistic mechanism, reducing systemic toxicity while overcoming physiological barriers to establish an efficient platform for precision oncology.

2.6.3. Iron oxide nanoparticles

Iron oxide nanoparticles (IONPs) catalyze decomposition of TME hydrogen peroxide (H₂O₂) via Fenton reactions, generating cytotoxic hydroxyl radicals (·OH) [29,62]. This significantly elevates intracellular ROS, overwhelms antioxidant defenses, and triggers irreversible oxidative damage [40,63].

In non-small cell lung cancer (NSCLC) therapy, SPIONs leverage their magnetic responsiveness and surface modifiability to achieve exosome-specific binding. This magnetic targeting strategy retains exosomes’ natural tumor homing while enabling precise nanoparticle enrichment in tumor tissue under external magnetic guidance, effectively promoting DOX aggregation at tumor sites [64]. Experimental data demonstrate that SPIONs co-loaded with DOX synergistically induce oxidative stress in MCF-7 cells while reduce toxicity to healthy tissues. This dual-targeted platform shows significant promise for DOX-based chemotherapy. In vitro studies of DOX-conjugated ferromagnetic nanoparticles in human breast cancer models reveal that DOX-loaded magnetic nanoparticles induce redox imbalance in MCF-7 cells, manifesting as: DNA damage, lipid peroxidation, cell membrane disruption, and mitochondrial depolarization [65]. Consequently, these nanoparticles effectively deliver DOX to MCF-7 cells, inducing cell cycle arrest and suppressing migration. The IONP platform significantly reduces toxicity to healthy cells while enhancing therapeutic outcomes, establishing a promising anticancer drug delivery strategy [40].

3. TME-based nanocarriers for delivery of DOX

3.1. TME

The TME is a complex ecosystem comprising tumor cells, stromal cells, immune cells, vasculature, and extracellular matrix (Figure 1) [66]. The interplay of these components drives multifaceted biochemical interactions. Accumulating evidence demonstrates that the TME critically regulates tumor progression, invasion, metastasis, and therapeutic resistance [67–69].

The TME is characterized by acidic pH, hypoxia, immunosuppression, pathological vasculature and the abnormality of ECM, primarily driven by the high glycolytic flux of tumor cells (Warburg effect) [66]. Excessive lactate production from aerobic glycolysis acidifies the microenvironment (pH 6.5–6.9), impairing drug efficacy and immune cell function. This immunosuppression creates a tumor-promoting feedback loop: dysfunctional cytotoxic T lymphocytes and tumor-associated macrophages (TAMs) fail to eliminate malignant cells, thereby accelerating tumor proliferation and metastatic progression. The pathological cascade of tumor vascular abnormalities establishes a pro-metastatic microenvironment through hypoxia-mediated metabolic adaptation. Aberrant angiogenic signaling culminates in structurally defective vasculature characterized by endothelial discontinuity and impaired perfusion, thereby perpetuating a hypoxic niche. At the molecular level, hypoxia-inducible factor 1α (HIF-1α) undergoes stabilization under oxygen deprivation (<2% O₂), orchestrating a transcriptional program that potentiates malignant progression through dual mechanisms. This hypoxia-HIF axis creates an evolutionary bottleneck favoring clonal expansion of therapy-resistant cancer stem cells (CSCs) with enhanced DNA repair capacity and ABC transporter overexpression [70]. Clinical implications of this hypoxia-CSC nexus manifest as MDR across therapeutic modalities. Radiotherapy efficacy diminishes due to oxygen-dependent free radical generation constraints, while chemotherapeutic agents fail to eradicate quiescent CSC reservoirs protected by hypoxia-induced dormancy. Emerging evidence further implicates HIF-1α in immune evasion through programmed death-ligand 1 (PD-L1) transactivation and regulatory T cell recruitment [71,72]. Nevertheless, challenges persist in achieving tumor-specific hypoxia modulation without disrupting physiological oxygen homeostasis, underscoring the need for spatially resolved delivery systems and real-time hypoxia imaging technologies.

3.1.1. Acidic environment

The TME is pathologically characterized by sustained acidosis, typically exhibiting pH values between 6.2 and 6.9, in stark contrast to the physiological pH homeostasis of normal tissues (~7.4) [73–76]. This acidic signature arises from the metabolic reprogramming of cancer cells, which preferentially rely on aerobic glycolysis (the Warburg effect) for energy production even under oxygen-sufficient conditions [77]. Through this metabolic adaptation, tumor cells generate excessive lactic acid as a byproduct of accelerated glycolysis. Concurrently, they overexpress proton-extruding transport systems, including monocarboxylate transporters (MCTs) and Na⁺/H⁺ exchangers (NHEs), which actively expel both lactate and protons into the extracellular space [78,79]. These coordinated processes establish a self-reinforcing cycle of acidification, progressively lowering the extracellular pH. The resulting acidic milieu profoundly impacts therapeutic outcomes through multiple interconnected mechanisms. Weakly basic chemotherapeutic agents, such as DOX, undergo pH-dependent ionization within the TME, leading to their sequestration in extracellular compartments and reduced intracellular accumulation – a phenomenon termed “ion trapping” [80]. Simultaneously, the acidic conditions impair immune surveillance by disrupting the functionality of cytotoxic T lymphocytes and polarizing TAMs toward immunosuppressive phenotypes.

These alterations collectively create a protective niche that enhances tumor cell survival and fosters therapeutic resistance. Current research strategies aim to counteract these effects through pharmacological inhibition of proton transporters and the development of pH-modulating nanotherapeutics, seeking to restore chemotherapeutic efficacy and immune cell activity within the TME.

3.1.2. Hypoxic environment

The disproportionate oxygen demand of neoplastic cells generates sustained hypoxia within the TME, stabilizing HIF-1α through PHD2/VHL pathway inhibition. HIF-1α dimerizes with HIF-1β, activating genes like LDHA and CAIX to enhance glycolytic ATP production, while vascular endothelial growth factor A (VEGFA) induction stimulates aberrant angiogenesis. This metabolic shift not only compensates for oxidative phosphorylation deficits but also fosters an immunosuppressive milieu by upregulating PD-L1 and recruiting regulatory T cells (Tregs). The hypoxic TME drives adaptive mechanisms that sustain malignancy. For instance, HIF-1α upregulates key glycolytic enzymes (e.g., hexokinase 2, LDHA) while suppressing mitochondrial oxidative phosphorylation, thereby enhancing tumor cell survival under oxygen deprivation [81–83]. Paradoxically, HIF-1α-mediated hypoxia also induces functional impairment and structural abnormalities in adjacent normal tissues, compromising their metabolic homeostasis. Concurrently, hypoxia triggers extracellular matrix (ECM) remodeling via lysyl oxidase (LOX)-mediated collagen cross-linking, creating a dense physical barrier that impedes cytotoxic T lymphocyte infiltration and facilitates immune evasion [84,85]. These dual effects – fueling tumor proliferation while disrupting normal tissue function – underscore hypoxia as a defining feature of the TME.

3.1.3. Immunosuppression

The TME is enriched with immunosuppressive components, including Tregs, myeloid-derived suppressor cells (MDSCs), TAMs, and soluble mediators such as transforming growth factor-beta (TGF-β), interleukin-10 (IL-10), and PD-L1. These elements collectively establish an immunosuppressive milieu that fosters tumor progression through dual mechanisms: enhancing malignant cell survival and subverting antitumor immunity.

Tregs and MDSCs constitute the predominant immunosuppressive cell populations within the TME. These cells suppress effector T cell functionality through the secretion of immunosuppressive cytokines, including IL-10 and TGF-β, thereby facilitating tumor immune evasion [86–88]. The immunosuppressive axis driven by PD-L1/PD-1 interactions demonstrates spatial heterogeneity within tumors, with 3.2-fold higher expression in hypoxic regions compared to normoxic areas [89]. Similarly, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) blockade via ipilimumab restores CD28-mediated costimulatory signaling, increasing CD8⁺ T cell tumor infiltration by 40–60% in melanoma models [90]. These findings demonstrate that dual immune checkpoint blockade mitigates cytokine-driven immunosuppression, highlighting its potential for clinical translation in cancer immunotherapy [87,91,92]. In the immunosuppressive TME, immune cells exhibit dynamic phenotypic and functional reprogramming. A prominent example is the polarization of TAMs from an antitumor M1 phenotype to a protumor M2 phenotype [93,94]. M2-type TAMs orchestrate immunosuppression by secreting IL-10 and TGF-β, which inhibit cytotoxic T lymphocyte activity while promoting angiogenesis and extracellular matrix remodeling. These mechanisms collectively drive tumor cell proliferation, invasion, and metastatic dissemination. PD-L1 expressed on tumor cells binds PD-1 receptors on cytotoxic T lymphocytes, inducing T cell exhaustion – a state marked by diminished Interferon-γ (IFN-γ) production and upregulated exhaustion markers, such as T cell immunoglobulin domain and mucin domain-3(TIM-)3, lymphocyte activation gene-3 (LAG-3) [95,96]. Concurrently, adenosine generated by CD73/CD39 ectoenzymes suppresses natural killer (NK) cell cytotoxicity and promotes angiogenesis via A2A receptor signaling. Tregs, characterized by FoxP3⁺ expression, suppress effector T cell activity via CTLA-4 engagement and adenosine secretion, reducing CD8⁺ T cell proliferation [97]. Similarly, MDSCs inhibit dendritic cell maturation through arginase-1-mediated L-arginine depletion, while TAMs polarized to an M2 phenotype secrete matrix metalloproteinases (MMPs) to facilitate metastatic niche formation [98,99]. Soluble factors like TGF-β further induce epithelial-mesenchymal transition (EMT), enhancing tumor invasiveness and chemoresistance [100].

This self-reinforcing system amplifies the recruitment and activation of immunosuppressive cells (e.g., Tregs, MDSCs) while driving the secretion of inhibitory factors (e.g., TGF-β, IL-10), thereby perpetuating a feedforward loop that sustains tumor immune evasion.

3.1.4. Pathological vasculature

The spatiotemporal coordination of vascular development depends on the precise regulation of the vascular endothelial growth factor (VEGF) signaling pathway. VEGF, a secretory polypeptide, is produced by hypoxic tissues through the activation of HIF transcription factors [101]. Functioning as an α/β heterodimer transcription factor, HIF dynamically regulates VEGF expression by sensing intracellular oxygen concentration. In the hypoxic microenvironment, the stability of the HIF-α subunit is enhanced. After binding to HIF-β, the dimer initiates VEGF gene transcription and forms an oxygen-sensitive angiogenesis switch [102,103]. This mechanism ensures that angiogenesis is initiated only in hypoxic regions and, through the binding of VEGF to the surface receptors of vascular endothelial cells, activates the regulatory processes of endothelial cell proliferation, migration, and permeability, representing the core steps of angiogenesis and maintaining homeostasis [104]. Tumor cells and stromal cells, such as cancer-associated fibroblast cells (CAFs) abnormally secrete pro-angiogenic factors such as VEGF and FGF in TME [105,106], disrupting the balance between angiogenesis and maturation and inducing the formation of a neovascular network with incomplete basement membranes and disordered branches [107,108]. Such blood vessels exhibit significant leakage characteristics due to loose endothelial cell connections, resulting in increased interstitial fluid pressure and intensified local hypoxia. Subsequently, a positive feedback loop is formed through HIF-1α-mediated VEGF resecretion, continuously driving vascular structural malformations and dysfunctions. Disordered blood perfusion further deteriorates hypoxia, forming a malignant tumor-promoting cycle. Tumor-associated immune cells are deeply involved in vascular function regulation through paracrine signals: Inhibitory factors such as TGF-β and IL-10 secreted by Treg cells can reduce the expression of vascular endothelial tight junction proteins and enhance vascular leakage [109,110]. Proteases such as MMP-9 released by TAMs directly degrade the components of the vascular basement membrane and promote pathological vascular budding [108].

This immune-vascular interaction not only aggravates vascular abnormalities but also fosters the immunosuppressive microenvironment by disrupting the vascular barrier function, establishing a bidirectional malignant regulatory network that promotes angiogenesis and immune escape.

3.1.5. Aberrant ECM reprogramming

Pathological remodeling of the ECM represents a defining characteristic of TME heterogeneity. During tumor progression, abnormal deposition of collagen and LOX-mediated cross-linking significantly enhances matrix stiffness [111]. This creates a physical barrier that impedes drug penetration. Concurrently, the integrin-YAP/TAZ mechanotransduction pathway activates EMT [104,112]. CAF-endothelial cell interactions amplify this vicious cycle: CAF-derived factors (e.g., TGF-β) drive ECM remodeling and release sequestered growth factors like VEGF [106]. Notably, vascular leakage-induced lactic acid establishes metabolic symbiosis with ECM reprogramming, promoting endothelial glycolysis via MCTs and accelerating pathological angiogenesis [113]. These alterations collectively establish a physicochemical-metabolic interplay network that drives tumor invasion, making remodeled ECM a hallmark of TME. Conversely, ECM degradation exhibits functional duality in tumor progression. Tumor cells secrete MMPs to hydrolyze key components (e.g., type IV collagen, fibronectin), facilitating physical routes for invasion [114]. Yet excessively dense ECM impedes drug delivery, causing subtherapeutic intratumoral drug concentrations. Selective degradation with hyaluronidase or LOXL2 inhibitors significantly enhances nanomedicine penetration and radiosensitivity [115]. This necessitates precise targeting to balance metastasis risks against therapeutic sensitization.

In summary, pathological ECM remodeling promotes invasion through stiffening, mechanotransduction activation, and metabolic coupling. ECM degradation exhibits metastasis-promoting and therapy-sensitizing dual effects. Precise regulation of degradation targets is essential to resolve this dichotomy and advance novel antitumor strategies.

3.2. The strategy of reshaping TME with DOX-loaded nanocarriers

DOX has been widely employed as a chemotherapeutic agent for multiple cancer types. However, free DOX lacks tumor-targeting specificity, leading to systemic toxicity and collateral damage to healthy tissues during tumor cell eradication. To address these limitations, current research integrates DOX with chemotherapy or radiotherapy to enhance synergistic efficacy, or engineers nanoscale drug delivery systems (NDDS) to achieve tumor-selective drug accumulation (Table 2). These nanocarriers exhibit high biocompatibility, biosafety, and tumor-targeting capabilities. Preclinical studies reveal that DOX-loaded nanocarriers not only enable tumor-selective drug delivery but also remodel the immunosuppressive TME during tumor cell eradication (Figure 3). This dual mechanism – simultaneously disrupting the TME and inducing cytotoxic effects – synergistically enhances therapeutic outcomes.

Table 2.

Nanocarrier strategies for DOX-mediated tumor micro-environment reprogramming.

TME Reprogramming Action	Strategy	Tumor Inhibition	Ref.
Adjust Acidic environment	A flexible liposomal system loaded with NaHCO3 can also synergize with PD-1 antibody therapy.	>80%	[116]
Alleviate TME hypoxia	Constructing the pH-responsive oxygen self-sufficient smart nanomedicine to prevent premature drug leakage and overcome hypoxia.	>95%	[117]
	Ultrasound trigger the oxygen release from PFC and excite DOX to ealize chemo-sonodynamic therapy.	>85%	[118]
Reverse TME immunosuppression	Utilizing liposome drug delivery system to load oxygen carriers, forming FA-L@MD@CAT to enhance the synergistic therapy.	>80%	[119]
Reverse vascular abnormalities of TME	Cytotoxic impacts of DOX and inhibits angiogenesis by VEGF-A siRNAs with excess immunologic benefits from DC-EVs.	>85%	[120]
Reverse the abnormality of ECM	Hydrolyze the collagen in ECM and enhance the permeability of DOX to the pancreatic tumor.	93.5%	[121]
	The delivered siRNA reduces the expression of the HGF in the remaining CAFs.	>80%	[122]

Figure 3.

Mechanism of therapy for cancer.

3.2.1. Adjust the pH value of the TME

An acidic pH of the TME will affect the surrounding normal cells, inhibit their normal metabolism, growth and proliferation, and be beneficial to the physiological activities of tumor cells. Therefore, based on the acidic environment of the TME, pH-responsive nanocarriers can be designed to release alkaline substances (such as sodium bicarbonate) in the acidic environment of the TME [123,124].

The pH-responsive nanocarrier exerts dual therapeutic effects by selectively neutralizing tumor-associated acidosis to restore physiological pH levels (7.2–7.4) [125], thereby suppressing glycolytic metabolism in cancer cells and enhancing stromal cell viability. Simultaneously, its pH-sensitive design enables targeted DOX release within acidic tumor regions through polymer degradation, ensuring localized cytotoxicity while minimizing systemic drug exposure in healthy tissues. This combined strategy disrupts the Warburg effect-driven energy production in malignancies and achieves tumor-selective drug activation, effectively balancing therapeutic efficacy with reduced off-target toxicity. Peng et al. [116] engineered a pH-responsive nanocarrier co-encapsulating DOX and sodium bicarbonate (NaHCO₃) to synergistically enhance antitumor efficacy through TME modulation. This system neutralizes acidic TME conditions, reversing DOX protonation to improve its cellular uptake and intracellular accumulation. The pH normalization further enhances drug permeability across tumor cell membranes while reducing off-target effects. Additionally, when combined with PD-L1 antibody therapy, the nanocarrier amplifies antitumor immunity by counteracting T cell exhaustion, leading to significant suppression of tumor cell proliferation [89]. This dual-action strategy highlights the potential of TME-targeted nanocarriers to integrate chemotherapy and immunotherapy for improved therapeutic outcomes.

3.2.2. Alleviate TME hypoxia

The hypoxic TME, characterized by oxygen partial pressure levels below 5 mmHg, is a hallmark feature arising from the metabolic demands of rapidly proliferating tumor cells and aberrant vascularization. This hypoxic niche differentiates malignant tissues from normoxic healthy tissues, providing a biochemical basis for targeted therapeutic strategies. Hypoxia-responsive nanocarriers exploit this unique condition by selectively delivering DOX to hypoxic tumor regions. These systems utilize hypoxia-sensitive triggers (e.g., nitroreductase enzymes or HIF-responsive promoters) to release DOX specifically within the TME, thereby minimizing systemic exposure and reducing off-target toxicity to healthy cells. By coupling hypoxia-selective drug activation with tumor-targeted delivery, such nanocarriers enhance therapeutic specificity while preserving normal tissue function, exemplifying a precision medicine approach to cancer treatment [119,123]. The hypoxic nature of the TME drives the development of oxygen-modulating nanocarriers. These systems are typically engineered by incorporating catalase (CAT) or perfluorocarbon (PFC). CAT enzymatically decomposes tumor-associated hydrogen peroxide (H₂O₂) into molecular oxygen (O₂), while PFC acts as an oxygen reservoir due to its high gas solubility. The H₂O₂ generated by tumor cells serves as a substrate for CAT-mediated oxygen production, while PFC-based nanocarriers directly deliver oxygen molecules to replenish the hypoxic TME. This combined oxygenation strategy elevates intratumoral oxygen levels, suppressing HIF-1α signaling and thereby reducing cancer stem cell viability and chemoresistance. Zheng et al. [126] have developed a copper ion-integrated MOF co-encapsulating DOX and CAT. In this system, Cu^{2 +} ions catalyze the decomposition of tumor-overexpressed H₂O₂ into O₂, increasing the local pO₂ from 5 mmHg to 25 mmHg and suppressing metastasis in triple-negative breast cancer. Together, these components enhance intratumoral oxygenation, alleviating hypoxia to improve therapeutic outcomes and mitigate hypoxia-driven resistance mechanisms [117–119].

The hypoxic TME provides a biochemical rationale for hypoxia-responsive nanocarriers, which enable tumor-selective DOX release through hypoxia-triggered activation to minimize systemic toxicity. Concurrently, these systems alleviate hypoxia by generating oxygen, disrupting TME homeostasis through suppression of the HIF-1α/PD-L1 signaling axis and chemoresistance pathways. This dual-action strategy – combining targeted drug delivery with TME remodeling – enhances intratumoral drug efficacy while preserving normal tissue function, exemplifying precision medicine to overcome hypoxia-mediated therapeutic resistance.

3.2.3. Reverse TME immunosuppression

The TME is characterized by systemic immunosuppression, primarily driven by overexpressed immunosuppressive mediators such as TNF-α, TGF-β, and IL-10. These cytokines directly impair effector T cell activation and promote Tregs expansion, while simultaneously dysregulating immune checkpoint pathways (e.g., PD-1/PD-L1). Collectively, these mechanisms establish an immunosuppressive niche that facilitates tumor immune evasion and therapeutic resistance [23,127–129]. For example, PD-L1, as an immunosuppressive factor, can bind to PD-L1 ligands, inhibit the proliferation and cytotoxicity of T cells, disrupt the anti-tumor immune response in the TME, and promote the generation of the immunosuppressive microenvironment at the tumor cell site [130]. Furthermore, the PD-1/PD-L1 signaling pathway also interacts with other cytokines. In tumor cells, PD-L1 activates the Jak2/Stat3 pathway by binding to PTP1B, drives IL-6 secretion, and promotes the formation and proliferation of MDSCs, jointly acting on the immunomodulatory pathways in the TME. Make the TME present an immunosuppressive state [131,132].

The immunosuppressive TME represents a strategic target for immunomodulatory nanocarriers loaded with DOX. These nanocarriers counteract TME-driven immunosuppression through two synergistic mechanisms: (1) pH- or enzyme-responsive drug release to achieve tumor-selective DOX delivery, and (2) immune checkpoint blockade via surface-conjugated anti-PD-L1 antibodies or TGF-β inhibitors, which disrupt immunosuppressive signaling pathways (e.g., PD-1/PD-L1 axis). By simultaneously enhancing cytotoxic T lymphocyte infiltration and suppressing regulatory Tregs activity, this dual-functional strategy reprograms the TME from an immunosuppressive to an immunostimulatory state, amplifying therapeutic efficacy while preserving systemic immune homeostasis [120,133]. A new strategy for reversing the immunosuppressive environment of the TME is the design direction of immune checkpoint blockade (ICB). Because there are immunosuppressive influencing factors such as Treg cell infiltration, M2-type macrophage polarization, and high expression of PD-L1 in the TME, it is possible to block immune signal transduction sites. The delivery of chemotherapeutic drugs induces the death of immunogenic cells (ICDs) or promotes the transformation of TAMs from type M1 to type M2 to secrete anti-inflammatory factors and inhibit tumor formation. Liu et al. [134] have studied and designed a protease-lysable liposome loaded with DOX and PD-L1 antibody (anti-PD-L1), which could not only target and deliver DOX to the tumor site, reduce the damage of DOX to normal cells, and improve the utilization of DOX in the body, but also release anti-PD-L1 antibody. It could bind to PD-L1 and reduce PD-L1 in the TME to promote the proliferation and growth of T cells, which has also been confirmed by the results of the colorectal cancer model [135]. The design strategy of ICB nanocarriers for transporting DOX to tumor sites can achieve targeted transport of DOX and also slow down or even reverse the immunosuppressive environment of TME. This new type of nanocarrier has the ability to target TAMs, target DOX to the tumor site, reduce the damage of DOX to normal cells and block the immunosuppressive signaling pathway by loading immunomodulators (such as PD-1/PD-L1 inhibitors). This enables TAMs to polarize from type M2 (tumor-promoting) to type M1 (anti-tumor) [24], restore the T-cell immune function in the TME, enhances the immunotherapeutic effect in the TME environment, and provides assistance for DOX to better exert its effects in inducing ICD and anti-tumor [136,137].

3.2.4. Reverse vascular abnormalities of TME

Normal vascular development relies on precise VEGF signaling regulation. Under physiological conditions, hypoxic tissues produce VEGF via HIF transcription factor activation. In TME, however, cancer cells and stromal components (e.g., cancer-associated fibroblasts) aberrantly secrete pro-angiogenic factors (VEGF, FGF) [105], disrupting angiogenesis-maturation equilibrium. This promotes formation of immature neovasculature characterized by fragmented basement membranes and disorganized branching [138]. Such pathological vessels reinforce immunosuppression through compromised barrier function, establishing a bidirectional pro-angiogenic and immune-evasive network [139]. Novel DOX nanocarriers counteract this dysregulation by delivering HIF-α inhibitors or siRNA to block VEGF transcriptional activation. In glioma models, co-loaded DOX/VEGF-A-siRNA nanoparticles reduce VEGF-A levels from 166.00 ± 7.21 pg/mL to 77.50 ± 6.08 pg/mL (vs. DOX-only controls) [120]. This VEGF suppression reverses TME abnormalities, inhibiting endothelial cell proliferation, migration, and permeability regulation while normalizing vascular structure and function.

The nanoplatforms modulate immune-vascular crosstalk through dual mechanisms: (1) delivering Treg-targeting immunomodulators (e.g., anti-CTLA-4) to reduce immunosuppressive factor secretion and downregulate VEGF/CD31/MMP9 expression, thus mitigating vascular leakage [140]; (2) inhibiting MMP-9 to prevent basement membrane degradation and suppress aberrant angiogenic sprouting [141]. Collectively, DOX-loaded nanocarriers reverse tumor vascular abnormalities through VEGF pathway targeting and immune-vascular interaction modulation, disrupting pro-tumorigenic cycles. While promising, current evidence remains preclinical; rigorous clinical validation of efficacy and safety profiles is warranted prior to therapeutic translation.

3.2.5. Reverse the abnormality of ECM in TME

CAFs drive pathological remodeling of the tumor ECM, creating dense structural barriers that severely restrict nanomedicine penetration into deep tumor regions and diminish therapeutic outcomes [142,143]. To address this challenge, developing nanocarriers capable of reprogramming aberrant ECM microenvironments becomes essential for advancing treatment efficacy [135].

Polypyrrole nanoparticles (PPy NPs) are synthesized through template-guided chemical oxidation. DOX is loaded into their porous architecture, followed by sequential functionalization with heat-sensitive lauric acid (LA) and surface-immobilized bromelain (BL) to construct PLB (PPy-LA-BL) NPs [121]. The engineered particles effectively degrade intratumoral collagen, enhance DOX permeation in pancreatic malignancies, and concurrently enable dual photothermal conversion and photoacoustic imaging capabilities for precision tumor ablation. In a complementary approach, researchers have designed MMP-2-responsive dual-targeting nanoparticles (HA-DOX@GNPs-Met@HFn) that underwent tumor-triggered size reduction from 124 nm to 36 nm [143]. Following enzyme-mediated cleavage, metformin modulates tumor cells via AMPK pathway activation to suppress TGF-β expression and inhibit CAF-driven ECM deposition. Simultaneously, the hyaluronic acid-conjugated DOX prodrug achieves deep tissue infiltration with subsequent intracellular enzyme-activated drug liberation [122,142]. This coordinated size-transition strategy coupled with ECM depletion markedly increases tumoral DOX bioavailability and chemotherapy effectiveness. Collectively, CAF-mediated ECM abnormalities establish significant treatment barriers. The described nanoplatforms reveal promising capacity for TME reprogramming, offering innovative methodologies to amplify DOX’s anticancer potential. Subsequent investigations warrant carrier optimization, mechanistic exploration, and expedited clinical implementation.

4. Conclusions

The occurrence of cancer is not only related to the corresponding tumor cells, but also a linkage reaction of a complex life system. In the TME at the site where cancer occurs, in addition to tumor cells, there are also many non-cancer cells such as immune cells, endothelial cells, cancer-associated fibroblasts and various other tissue cells [144]. These cells are regulated through metabolic activities and jointly act on the TME through various signaling pathways and the secretion of different signaling factors.

The TME, due to the strong reproductive ability of tumor cells and abnormal metabolic regulation, combined with the metabolic activities of other cells and cytokine regulation, has characteristics such as low pH value, oxygen deficiency and suppressed immune response in the TME. The TME under such characteristics is suitable for the growth and proliferation of tumor cells, but has an inhibitory effect on the normal physiological activities of non-cancer cells. DOX, as a typical anti-tumor drug, has a strong tumor-killing ability. However, it lacks tumor-targeting function and often damages other normal cells while killing and eliminating tumor cells [2,11]. Due to the high reproductive capacity and strong metastasis ability of tumor cells, it is difficult to cure tumor cells through simple oral medication [145–148]. In order to better exert the anti-tumor effect of DOX, nanocarriers are often used to target and deliver DOX, and are combined with other treatment methods to act on tumor cells together, so as to exert a better anti-tumor effect. Advances in nanomedicine have yielded diverse tumor-targeted delivery systems – such as liposomes, polymeric micelles, metal-organic frameworks (MOFs), and biomimetic nanoparticles – to optimize DOX delivery while minimizing systemic toxicity [20,22,33,54]. These nanocarriers exploit either intrinsic material properties (e.g., pH-responsive degradation) or engineered surface modifications (e.g., ligand conjugation) to achieve TME-triggered drug release. This spatial control enhances intratumoral DOX accumulation and cytotoxic efficacy, while significantly reducing off-target effects on healthy tissues.

With the research and development of tumor cells and the further in-depth development of the DOX targeted delivery system, nano-delivery carriers with a dual-functional design of “targeted drug release -TME regulation” have emerged [136,149]. Most of these nanocarriers, while having the function of targeted delivery of DOX, can also carry drugs with other functions. Together with the complex metabolic regulatory system in the TME, they act on tumor cells or immune cells, inhibiting the metabolism, growth and proliferation of tumor cells.

5. Future perspective

This article mainly introduces a new type of nanocarrier that can exert a synergistic effect by regulating the TME. While loading DOX to the tumor site, it reverses or slows down the promoting effect of the TME on the proliferation and metabolic activities of tumor cells through the regulation of various functions. This kind of nanocarriers can establish different signal response mechanisms according to different needs, such as responding to multiple TME signals such as pH, hypoxia, immunosuppressive factors, vascular abnormalities and the abnormality of ECM [20,120,143,150–152]. Dynamic regulation of drug release is conducive to promoting the research process of targeted delivery of DOX, promoting personalized treatment, and providing possibilities for clinical treatment. In the future, with the in-depth understanding of the mechanism of TME and the continuous development of nanocarrier research, DOX nanocarriers based on TME are expected to bring new breakthroughs to tumor treatment.

Funding Statement

This paper was not funded.

Article highlights

• This review systematically summarizes four major delivery systems for doxorubicin, including liposomes, metal-organic frameworks (MOFs), micelles, and biomimetic nanocarriers.

• The antitumor mechanisms of DOX are detailed, and the therapeutic performances of various nanocarriers are comparatively analyzed.

• A comparative overview is presented to illustrate how different nanocarriers overcome TME-associated barriers and improve antitumor therapeutic outcomes.

Author contributions

Weibo Kong: Investigation, Drawing, Writing-original draft. Weijun Chen: Writing – review & editing, Jing Hui: Investigation, Resources, Lipeng Qiu: Conceptualization, Supervision, Writing – review & editing.

Disclosure statement

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.