Nanocarrier strategies to overcome P-glycoprotein-mediated drug resistance in cancer therapy

Nanomedicine strategies for overcoming multidrug resistance in breast cancer: recent advances and future perspectives

Overall, nanomedicine offers a multifaceted and promising approach to overcome MDR in breast cancer; however, further translational and clinical studies are required to fully realize its therapeutic potential.

Paclitaxel Nanomedicines: Molecular Mechanisms of Drug Resistance, Tumor Microenvironment-Responsive Delivery, and Translational Challenges

Paclitaxel (PTX) remains a major component of treatment for solid tumors, but its clinical performance is limited by poor aqueous solubility, solvent-associated toxicity, heterogeneous tumor exposure, and multifactorial drug resistance. This narrative review examines PTX nanomedicines from a molecular pharmacology perspective, focusing on how carrier design interacts with resistance pathways, tumor microenvironment signals, and intracellular drug trafficking. We outline resistance mechanisms involving ATP-binding cassette subfamily B member 1 (ABCB1)/P-glycoprotein (P-gp)-mediated efflux, microtubule remodeling, apoptosis-related signaling, epigenetic regulation, extracellular matrix deposition, hypoxia, and redox imbalance. We evaluate albumin-bound formulations, liposomes, polymeric micelles, stimuli-responsive carriers, biomimetic systems, carrier-free prodrug assemblies, and multidrug co-delivery platforms according to the molecular and biological barriers they address. Particular attention is given to pH-, redox-, enzyme-, and hypoxia-responsive release; tissue penetration and subcellular localization; and co-delivery of PTX with chemosensitizers, nucleic acids, or pathway-directed agents. Molecular simulation and machine learning are considered as tools for formulation optimization and biomarker-guided patient stratification. These approaches can coordinate drug exposure and resistance modulation in preclinical models, but clinical benefits remain inconsistent. Translation will require reproducible formulations, clinically predictive models, direct measurement of intratumoral drug levels, and validated biomarkers linking molecular delivery mechanisms to patient outcomes.

Bioactive nanomedicines for multidrug-resistant colorectal cancer: Actionable mechanisms, emerging particle classes, and translational barriers.

Multidrug resistance (MDR) in colorectal cancer (CRC) arises from interacting tumour-cell, pharmacological and microenvironmental programmes that undermine both drug activity and delivery. Chemotherapy-associated MDR is the principal focus of this review, while resistance to targeted therapy and immunotherapy is considered where it directly affects delivery design or patient selection. Bioactive compounds can modulate several resistance pathways, but their translational value is constrained by poor solubility, instability, rapid metabolism and inadequate exposure at resistant lesions. This review critically examines when nanomedicine can make such mechanistic activity pharmacologically and translationally meaningful. We link resistance biology to delivery functions, evaluate bioactive chemosensitiser candidates against human exposure, compare major nanomedicine design strategies, and assess nano-bio interactions, repeat-dose safety, manufacturing and clinical positioning. Across the evidence, three limitations recur. First, concentrations associated with chemosensitisation for curcumin, resveratrol, epigallocatechin gallate and quercetin generally exceed measured human parent-analyte exposure. Second, many resistance claims rely on parental or poorly characterised models, whereas studies combining defined resistance provenance with functional mechanism and exposure confirmation remain uncommon. Third, human studies demonstrate feasibility, tissue exposure or treatment response, but not mechanism-specific reversal of CRC MDR by a bioactive compound or bioactive nanomedicine. Progress therefore depends less on adding new particle classes than on matching a necessary formulation function to a defined resistance or spatial barrier, quantifying active exposure in the relevant compartment, validating mechanism in appropriate models, and integrating repeat-dose safety, scalable manufacturing and biomarker-guided clinical development.

Biomimetic delivery systems for overcoming drug resistance in gastrointestinal cancers.

By linking GI cancer-focused MDR biology to function-oriented biomimetic design, this review establishes an evidence-based framework for distinguishing delivery enhancement from true MDR reversal and outlines platform-specific requirements for clinical translation.

BLU-945 suppresses ABCB1-mediated drug efflux and restores chemosensitivity in multidrug-resistant cancer cells.

THERAPEUTIC ROLE OF siRNA IN GASTRIC CANCER: GENE SILENCING MECHANISMS AND NANOCARRIER-BASED DELIVERY STRATEGIES.

Gastric cancer (GC) continues to be a significant global contributor to cancer-related mortality, primarily due to late-stage diagnoses, tumor heterogeneity, and the frequent emergence of therapeutic resistance. Despite advancements in surgical techniques, chemotherapy, targeted therapies, and immunotherapy, long-term survival rates remain unsatisfactory, underscoring the need for innovative, molecularly driven approaches. SiRNA has emerged as a promising gene-silencing tool capable of selectively downregulating oncogenic drivers and pathways associated with resistance via RNA interference. Preclinical studies using GC models demonstrate promising biological activity following siRNA-mediated suppression of various molecular targets - including CD44v6, Rac1, and ZNRD1-leading to reduced cell proliferation, inhibited migration and invasion, enhanced apoptosis, and increased chemosensitivity. However, the successful translation of siRNA-based strategies into clinical practice is fundamentally reliant on the development of efficient and safe delivery systems. Recent advancements in nanotechnology have enabled the development of multifunctional nanocarriers, including lipid-based nanoparticles, peptide-based systems, chitosanderived platforms, exosome-mimetic vesicles, layer-by-layer architectures, and stimuli-responsive theranostic nanoparticles. These engineered platforms are designed to enhance siRNA stability, improve tumor targeting, facilitate intracellular trafficking, and promote endosomal escape while minimizing off-target effects and immune activation. Preclinical findings suggest significant biological potential; however, additional research is required to address issues concerning biodistribution, safety, scalability, and regulatory standardization before clinical application. Overall, siRNA-based strategies may play a crucial role in the future development of precision-oriented therapeutic frameworks in GC research. Importantly, this review emphasizes the integration of molecular target selection with delivery system design in a GC-specific context. By systematically linking validated siRNA targets with corresponding nanocarrier strategies, this work provides a more application-oriented and translationally relevant perspective that is not typically addressed in conventional RNA interference or nanocarrier-focused reviews.