Chemoresistance remains the primary cause of cancer treatment failure, yet current understanding remains fragmented across isolated mechanistic studies. This review provides a unified framework linking tumor microenvironment (TME) signaling, epigenetic reprogramming, and nanotherapeutic intervention as an integrated axis driving and potentially reversing chemoresistance. We systematically examine how TME components: hypoxia (HIF-1α pathway), acidosis, cancer-associated fibroblasts (TGF-β/PDGF signaling), and immune cells (NF-κB-mediated immunosuppression) activate signaling cascades that directly interface with epigenetic machinery. These TME-activated pathways recruit DNA methyltransferases, histone-modifying enzymes, and regulate microRNA (miRNA) networks, establishing stable resistant phenotypes including epithelial-mesenchymal transition, cancer stem cells, and metabolic adaptation. Critically, miRNA dysregulation serves as a central integrator, creating bidirectional crosstalk between signaling pathways and epigenetic modifications through self-reinforcing circuits. Unlike previous reviews focusing on isolated resistance mechanisms, we demonstrate how this integrated TME-epigenetic axis creates specific therapeutic vulnerabilities exploitable through rationally designed nanotechnology platforms delivering epigenetic modulators (DNMT inhibitors, HDAC inhibitors, EZH2 inhibitors) and gene therapy tools (CRISPR-Cas9 epigenetic editors, miRNA mimics/antagomirs). We critically evaluate clinical translation challenges, including EPR effect heterogeneity, delivery barriers, and biomarker gaps, providing a balanced perspective on both potential and obstacles. This mechanistic framework guides the development of next-generation combination therapies targeting multiple nodes within the TME-epigenetic-nanotherapy axis.

Currently, single-modal tumor therapy has significant limitations, while multi-modal combination therapy can overcome this bottleneck and open up new pathways for enhancing the efficacy of tumor therapy. However, it is still difficult to design a functionalized nanocarrier that can simultaneously mediate multiple therapeutic approaches. To tackle this challenge, we developed a multifunctional nano-codelivery system with glucose oxidase (GOx) loaded inside iron-doped zeolitic imidazolate framework-8 (Fe/ZIF-8), abbreviated as GFZ. This system effectively integrates the synergy and complementarity between ferroptosis therapy and starvation therapy (STT). Herein, GFZ innovatively combines the pH sensitivity of the ZIF-8 skeleton with the EPR effect of nanoparticles to achieve on-demand triggered release, significantly improving the accuracy of tumor targeting. Furthermore, GOx-mediated STT effectively alleviates the insufficiency of endogenous H2O2 during the ferroptosis process, thereby enhancing and synergizing with ferroptosis therapy. Experiments demonstrated both in vitro and in vivo that GFZ activates antitumor cascade reactions, inhibits tumor recurrence and metastasis, and exhibits excellent biocompatibility. Consequently, given its remarkable potential, GFZ is poised to emerge as a new mode of nano-delivery platform.

Nanotechnology-based drug delivery systems have significantly advanced modern pharmaceutics by addressing limitations associated with conventional therapies, including poor solubility, rapid systemic clearance, and nonspecific drug distribution. Among various nanocarriers, liposomes remain one of the most clinically validated platforms due to their biocompatibility, structural similarity to biological membranes, and capacity to encapsulate both hydrophilic and lipophilic drugs. Despite extensive research, important translational challenges persist, including formulation stability, variability in tumor targeting via the EPR effect, manufacturing scalability, and immunogenicity associated with repeated dosing. This review provides an integrated and critical overview of liposome-based drug delivery systems, combining mechanistic insights, formulation design principles, preparation technologies, and clinical translation perspectives within a single framework. Particular emphasis is placed on recent advances in liposomal engineering strategies, including surface modification, stimuli-responsive systems, and scalable manufacturing approaches such as microfluidics. Clinically established formulations such as Doxil® and AmBisome® are highlighted as representative examples demonstrating improved therapeutic efficacy and reduced toxicity compared with conventional formulations. In addition, the review discusses emerging trends in next-generation liposomal systems, including targeted liposomes, RNA-delivery platforms, and hybrid lipid-polymer vesicles. By integrating formulation science with translational considerations and recent developments (2022-2025), this review provides an updated perspective on the evolving role of liposomes in nanomedicine and highlights key directions for future research and clinical development.

Flutamide-loaded potato starch-chitosan-lactoferrin nanoparticles (FLU-PS-CS-LF-NPs) were explored for targeted delivery against colorectal cancer therapy. The best nanoparticles, with a diameter of 186.8 ± 63.12 nm and a zeta potential of +5.77 ± 1.56 mV, showed passive tumor targeting via the EPR effect and enhanced mucoadhesion. Drug entrapment and physicochemical integrity were ascertained by spectroscopic investigations (FTIR, XRD, Raman, and NMR). Thermal and microscopic analysis established morphological homogeneity and a change in crystalline form, supporting enhanced solubility. MTT assay showed enhanced cytotoxicity against HCT-116 cells (IC50 = 6.77 μg/mL), and flow cytometry confirmed increased apoptosis and G2/M phase cell cycle arrest. Other results showed decreased ROS and mitochondrial damage, effective cellular uptake, and strong anti-metastatic activity. Antibacterial and fecal culture tests showed inhibition of CRC-associated microbiota, while biocompatibility tests established safety and nontoxicity. In vivo colon-targeting and pH-dependent delivery were achieved, and the formulation remained stable for 6 months. Results indicate that FLU-PS-CS-LF-NPs are a potential nanocarrier system for effective, safe, and targeted therapy of colorectal cancer.

Targeted drug delivery systems (TDDS) have become a revolutionary method in contemporary medicine, allowing drugs to be accurately targeted at the affected areas while reducing the side effects on the whole body. Nowadays, nanotechnology has played a huge role in creating the next generation of drug carriers including liposomes, polymeric nanoparticles dendrimers micelles, and solid lipid nanoparticles by making them more bioavailable, stable, and offering controlled drug release properties. These nanoscale carriers use passive targeting methods like the EPR (enhanced permeability and retention) effect while also relying on active targeting through ligand receptor interaction to localize drugs precisely at the disease site. In addition, the use of stimuli-responsive drug carriers that change their behaviour according to pH temperature enzymes, or redox also help in making therapy more accurate by unloading drugs at the diseased sites alone. A number of recent studies demonstrate dramatic therapeutic efficacy with targeted drug nanocarriers. For instance, antibody-conjugated Nano capsules led to a 4 times higher anticancer performance than drugs alone in animal models of pancreatic cancer. In the same vein, sophisticated nanonetwork-mediated transport systems enhanced the share of drug reaching the target cells by around 17%, whereas colon-specific nanoparticles were capable of encapsulating 83.5% of the drug and releasing 95.2% of it in the target area.

Introduction: The enhanced permeability and retention (EPR) effect is a pivotal mechanism that facilitates the accumulation of macromolecules and nanoparticles in solid tumors owing to abnormal vasculature and impaired lymphatic drainage. This phenomenon underpins the development of tumor-targeted nanomedicines. Methods: A comprehensive review of recent studies was conducted, focusing on nanoparticlemediated drug delivery that exploits the EPR effect. Special emphasis was placed on transdermal drug delivery systems (TDDS) integrated with nanoparticles for cancer therapy, highlighting their design, size range (10–500 nm), and multifunctional potential. Results: Evidence demonstrates that nanoparticles utilizing the EPR effect achieve enhanced accumulation and prolonged retention in tumor tissues while reducing the systemic toxicity. Transdermal nanoparticle systems enable sustained and controlled drug release, thereby improving bioavailability and patient compliance. Moreover, multifunctional nanoparticles show promise for simultaneous drug delivery, imaging, and targeted therapies. Discussion: The findings indicate that integrating EPR-based nanoparticle delivery with transdermal systems can overcome the limitations of conventional chemotherapy. These advances enhance therapeutic efficacy, minimize side effects, and represent a step toward noninvasive, patient- friendly cancer treatment approaches. Conclusion: The EPR effect, coupled with transdermal nanoparticle delivery, offers a promising platform for personalized cancer therapies. Continued innovations in nanotechnology are expected to further refine these systems, paving the way for effective, targeted, and safe cancer treatment.

Enhanced permeability and retention (EPR) effect: Advances in nanomedicine for improved tumor targeting.

According to the ER = EPR conjecture, entangled particles are connected by quantum wormholes. Under the assumption that some of the electric field surrounding an entangled charged particle leaks into the wormhole, we show that this effect will modify the hyperfine structure of the hydrogen atom. In addition, if the quantum wormholes are nontraversable, this will also lead to a nonzero total effective charge for the hydrogen atom. These effects provide strong constraints on the amplitude of this potential ER = EPR effect, given high-precision measurements of the hydrogen atom's hyperfine structure and total charge.

Cancer treatment remains challenging due to tumor heterogeneity, drug resistance, and the complex microenvironment that limits monotherapy efficacy. Herein, we report a glutathione (GSH)-responsive multifunctional nanodrug FeCe6@SKN that is self-assembled from the complex formed by the coordination of the photosensitizer Ce6, the natural anticancer agent Shikonin (SKN), and ferric ions (Fe3+). After tail vein injection, FeCe6@SKN can effectively accumulate at the tumor site through the EPR effect and subsequently disassemble by high concentration of GSH, leading to the controlled release of Fe2+, Ce6, and SKN. This GSH-triggered disassembly and resulting size reduction not only improve the tissue penetration ability of nanodrugs but also enhance the fluorescence signals as well as the singlet oxygen generation capacity of Ce6, enabling efficient photodynamic therapy (PDT). Shikonin simultaneously triggers cancer cell apoptosis by upregulating the pro-apoptotic protein Bax and downregulating the antiapoptotic protein Bcl-2. More notably, the excessive accumulation of intracellular iron ions induces ferroptosis and further suppress tumor growth. It is evidently demonstrated that this multimodal therapeutic approach that combines ferroptosis, PDT, and chemotherapy significantly reduces the drug dosage and improves the therapeutic efficacy. This work may provide a universal and promising approach for developing intelligent and tumor microenvironment-responsive nanodrugs for effective cancer therapy.

Nanotechnology is a scientific field where STS scholars have observed the influence of magical thinking. Here we contribute to that literature by describing a phenomenon in the field of drug delivery called the EPR (Enhanced Permeability and Retention) Effect. When the 'nano' boom of the 2000s brought intense interest from outside pharmacology, EPR spawned so many efforts and enterprises in nano-based drug delivery that it became the leading basis for nanomedicine's promise. Following the 2016 failure of a prominent nano-biotech firm exploiting EPR, the collapse of the field offers insights into the role such theories or narratives played in the formation of nanomedicine and, more broadly, how contemporary technoscience may incorporate elements of enchantment-particularly where exposed to financialization.

Smart nanocarriers have become revolutionary delivery platforms in targeted drug delivery due to the critical vulnerabilities of traditional methods of therapeutic delivery, such as low bioavailability, non-specific delivery, and off-target toxicity. This review will discuss the rational design, therapeutic strategies and the translational issues of stimuli-responsive nanocarrier systems that are developed to obtain spatiotemporal control of drug release. The use of organic (liposomes, dendrimers, polymeric micelles), inorganic (gold, silver, iron oxide, graphene derivatives) and high-order hybrid (lipid-polymer hybrids, cell membrane-coated biomimetic systems) nanoparticles is discussed. Principles of nanocarrier design, such as the mechanics of physicochemical properties (size, shape, surface charge), targeting (passive EPR effect, active ligand-mediated recognition), and stimulus-responsive mechanisms (endogenous (pH, enzymes, redox)) or exogenous (temperature, light, magnetic field) stimuli are critically discussed. The therapeutic uses include oncology, where nanocarriers overcome the multidrug resistance and the tumor microenvironment, infectious disease, neurological diseases, cardiovascular diseases and inflammatory/autoimmune disorders. Although there has been considerable preclinical advancement and more than 4,000 clinical trials, there are still translational challenges, such as formation of protein corona, reticuloendothelial clearance, scale of manufacturing, regulatory complexity and issues related to immunogenicity. New paradigms, which combine artificial intelligence-based design, microfluidic organ-on-chip devices and patient-specific computational modeling, have the potential to overcome these obstacles. This review offers a platform upon which a rational design of future smart nanocarriers can be attained by integrating progress in nanomaterial engineering with biological and regulatory factors to achieve the potential of precision nanomedicine.

Docetaxel (DTX) and several other taxanes are one of the most important class of anticancer chemotherapeutic agent. DTX commercially marketed as Taxotere® has higher clinical significance amongst other taxanes owing it a wide range of clinical applications. Although its broad range of applications and wide commercial use, its clinical use limited due to associated undesired side toxicity. Recent developments in nanotechnology has emerged with novel ways to overcome the limitations of DTX. Numerous nanocarrier system offer enhanced efficacy of DTX by utilizing EPR effect, tumor vascular hyperpermeability, reduced lymphatic drainage and raised interstitial fluid pressure in tumor cells. Furthermore, these systems can be actively transported via targeting over expressed receptors in tumor cells or via targeting tumor endothelium. This review covers a range nanocarrier based formulations of DTX used for in-vitro and in-vivo evaluation for several types of cancer. Although nanoformulations such as polymeric nanoparticles, lipidic nanoparticles or inorganic nanoparticles significantly enhance the solubility, efficacy and bio-distribution of DTX, important obstacles of nanoformulations such as quality control, stability (physico-chemical and physiological), industrial-scale manufacturing and technology, in-vivo fate (metabolism, excretion, and chronic toxicity) still remain a concern. Numerous supporting data and regulatory guidelines should be established regarding these concerns to make DTX nanoformulations applicable widespread clinically. Keywords: Docetaxel; Nanocarriers; EPR effect; Cancer therapeutics; Cancer drug resistance.

Near-infrared photoimmunotherapy (NIR-PIT) converts antibody-antigen binding into highly localized cytotoxicity through 690 nm light activation of an antibody-photoabsorber conjugate (APC). Distinct from photodynamic or photothermal modalities, NIR-PIT operates via photoinduced axial-ligand dissociation of IRDye700DX (IR700), which drives hydrophobic collapse, APC clustering on the plasma membrane, and rapid membrane disruption-termed photochemosis-without generating reactive oxygen species or causing bulk heating. Beyond immediate tumor debulking, NIR-PIT elicits immunogenic cell death (ICD) characterized by calreticulin exposure and ATP/HMGB1 release, and induces the super-enhanced permeability and retention (SUPR) effect that transiently increases intratumoral accumulation of macromolecules and nanodrugs by up to approximately 24-fold in particular in vivo models, compared with the baseline EPR effect. These distinct photochemical and immunological mechanisms provide a strong rationale for combinatorial strategies integrating NIR-PIT with immune checkpoint blockade, cytotoxic chemotherapy, nanomedicine, radiotherapy, and clinically relevant hyperthermia. This review summarizes the mechanistic basis of photochemosis, ICD, and SUPR, and discusses their translational applications, device innovations, and intersections with thermal biology, providing a conceptual framework for advancing photothermal-photoimmunological oncology.

The Active Transport and Retention (ATR) principle offers a new strategy to enhance tumor entry of nanodrugs via transcytosis. However, its application is limited by poor tumor-homing, endothelial polarized efflux, and uncontrollable transcytosis of the nanodrug. Herein, we construct a bio-mimetic micro-nano system (PG@BAM-LRC) comprising nanoliposomes (LRC) and berbamine (BAM) within platelet-derived microcarrier (PG), leveraging PG's tumor-homing ability and MMP-9 responsive remodeling for tumor-specific cargo release. Thereafter, BAM selectively promotes basal transendothelial transport of LRC toward the tumor by modulating apical recycling endosomes. While R8 promotes the cellular uptake, the arginine-lysine-lysine-arginine-cysteine (Cys) ligand facilitates Golgi-targeted transendothelial transport of LRC, bypassing the endo-lysosome pathway. Once inside tumor cells, furin-mediated Cys-cleavage halts transcytosis, yielding superior intracellular drug retention compared to the non-cleavable Cys counterpart (LRC'). Four murine tumor models are established, demonstrating high heterogeneity in collagen density, vascularity, and EPR effects. An orthotopic pancreatic tumor, characterized by minimal EPR effect, is selected to demonstrate the ATR effect of PG@BAM-LRC. PG@BAM-LRC loaded with BAY-872243 exhibits exceptional tumor accumulation and therapeutic outcome compared to LRC, PG@LRC without BAM, and PG@BAM-LRC. Collectively, this study establishes PG@BAM-LRC as a robust tumor-targeting system leveraging the ATR mechanism while addressing tumor heterogeneity.

Self-assembled multicomponent prodrugs with GSH/ROS site-responsiveness enable spatiotemporally controlled release for treating resistant NSCLC.

Photodynamic therapy (PDT) holds promise for oral squamous cell carcinoma (OSCC) but is limited by the tumor microenvironment─specifically hypoxia, elevated glutathione (GSH), and the lack of tumor-selective photosensitizer activation. To overcome these barriers, we developed a GSH-activated nanoplatform Cu-TCPP(Zn)/Ti3C2Tx for fluorescence imaging-guided synergistic photodynamic/chemodynamic therapy (PDT/CDT). The system is constructed from two-dimensional Cu-TCPP(Zn) MOF nanosheets, where Cu2+ and Zn2+ completely quench the fluorescence and PDT activity of TCPP and surface-anchored Ti3C2Tx MXene. In the TME, overexpressed GSH reduces Cu2+ to Cu+ and abstracts Zn from the Zn-N4 complex, triggering nanocomposite disintegration to restore fluorescence, activate PDT, and simultaneously deplete GSH to reduce antioxidant defense. The resulting Cu+ catalyzes a Fenton-like reaction with endogenous H2O2 to generate •OH for CDT, while Ti3C2Tx acts as a catalase-like nanozyme, decomposing H2O2 into O2 to alleviate hypoxia, promote charge transfer, improve the utilization efficiency of photogenerated electrons, and enhance PDT efficacy. In vitro, the platform showed excellent biocompatibility and GSH-responsive activation, inducing 41.21% apoptosis in CAL-27 cells under 660 nm laser irradiation, significantly outperforming controls. In vivo, the nanocomposite accumulated efficiently in tumors via the EPR effect, suppressed tumor growth, and exhibited no observable systemic toxicity. This work provides a TME-responsive theranostic platform that integrates tumor-specific activation, GSH depletion, hypoxia alleviation, and enhanced ROS generation for precise and effective OSCC treatment.

Photodynamic therapy (PDT) is a technique based on the use of photosensitizers activated by light to destroy cancer cells in the presence of oxygen. This enables localized cancer treatment and, in some settings, fluorescence-guided visualization. However, the efficacy and clinical translation of PDT have been limited by the low specificity of traditional photosensitizers. The aim of the study is to create a ligand-guided PDT approach for pancreatic ductal adenocarcinoma (PDAC) using a peptide-conjugated photosensitizer binding to integrin αvβ6, which is a receptor linked to tumor growth and prevalent in PDAC cells. Current treatment options for this tumor are limited, with surgical resection and chemotherapy only effective when the tumor is detected early. Given the limited treatment options for PDAC, PDT via αvβ6 offers a new pathway for precision treatment. The cyclic peptide cyclo[FRGDLAFp(NMe)K], recognized for its high affinity to αvβ6, was chosen to guide a phthalocyanine-class photosensitizer toward αvβ6-expressing PDAC models. The PDT approach was further refined by developing 3D spheroid models and in vivo BxPc3 xenograft models in NOD/SCID mice, where its therapeutic efficacy was assessed. In the absence of a non-targeted control photosensitizer, a contribution from non-specific accumulation and EPR effects in the in vivo setting cannot be fully ruled out. This study highlights the potential of a peptide-guided photosensitizer, demonstrating uptake and photodynamic activity in spheroids, with moderate in vivo results addressing tumor microenvironment challenges. Optimization of PDT dosing, laser precision, and preclinical models, such as patient-derived xenografts, are crucial to enhance clinical translation.

Precise targeting of the tumor micro-environment (TME) through nanotherapeutic innovations offers a transformative approach to cancer treatment. In order to increase the treatment efficacy, this review delves into the complex tactics for targeting different parts of the TME. Targeting the extracellular matrix, controlling acidosis and hypoxia, and preventing neovascularization by concentrating on pericytes and endothelial cells are important areas covered in this article. Strategies to stimulate anti-tumor immunity, regulate chronic inflammation, and restrict macrophage recruitment emphasize the immune system's participation. We have also highlighted the role of fibroblasts and exosomes linked to the cancer progression. The EPR effect, which is vital for cancer nanotherapeutics to work, and vascular pathophysiology are also included in the review. We examine how changes to the dynamics of pH inside the TME affect by nano-therapeutics. Additionally, the possibility of prodrug therapy within the TME, the use of controlled release mechanisms in nanocarriers to imitate metronomic therapy has been discussed. Lastly, the paper examines nanoparticle preference targeting as a potential strategy to improve treatment specificity and therapeutic efficacy in cancer management.

A multifunctional nanoplatform for dexamethasone delivery and dual-mode colorimetric/fluorescent sulfide ion detection to alleviate juvenile sepsis

Photothermal therapy (PTT) enables rapid and efficient in situ tumor eradication, and immunogenic cell death (ICD) induced by PTT enhances immune responses at tumor sites, achieving sustained tumor suppression and preventing recurrence. However, the low photothermal conversion efficiency and tumor-targeting capability of the photothermal agents limit PTT. Additionally, the highly expressed heat shock proteins (HSPs) in tumors compromise PTT. To address these limitations, a multifunctional tumor-specific carrier-free nanodrug, IG@PDA-FA NPs, was designed for combined chemo-PTT therapy. First, IG@PDA-FA NPs demonstrated a high encapsulation efficiency of up to 81.83% for Gambogic acid (GA) and 61.13% for Indocyanine green (ICG), and enhanced tumor accumulation through the EPR effect and folate receptor-mediated targeting. Second, compared to free ICG, IG@PDA-FA NPs significantly improved photothermal conversion efficiency (PCE) from 14.50 to 21.75% by an aggregation-caused quenching (ACQ) effect. Moreover, GA in IG@PDA-FA NPs not only induced apoptosis but also enhanced the PTT efficacy through HSP downregulation. IG@PDA-FA NPs promoted tumor ICD through the chemo-PTT effect, further activating cytotoxic T cells and promoting M2-to-M1 macrophage polarization at tumor sites. Ultimately, IG@PDA-FA NPs effectively suppressed tumor growth and metastasis by a combination of chemotherapy, PTT, and immunotherapy, offering a promising strategy for triple-negative breast cancer treatment.