Jul 2026· NEWPORT INTERNATIONAL JOURNAL OF SCIENTIFIC AND EXPERIMENTAL SCIENCES· Vol 7, pp. 140-145· 0 citations
TL;DR
A comprehensive and critical analysis of the biological basis of MDR in solid tumors, the design principles of stimuli-responsive nanomedicine, and their applications in overcoming drug resistance are provided.
Abstract
Multidrug resistance (MDR) remains one of the most formidable barriers to successful chemotherapy in solid tumors, accounting for the failure of many otherwise potent anticancer agents. MDR arises from a complex interplay of cellular, molecular, and microenvironmental mechanisms, including drug efflux transporter overexpression, altered drug metabolism, enhanced DNA repair, evasion of apoptosis, and tumor microenvironment–mediated protection. Conventional approaches to overcome MDR, such as dose escalation or combination chemotherapy, often exacerbate systemic toxicity without achieving durable responses. Stimuli responsive nanomedicine has emerged as a highly promising strategy to address these limitations by enabling spatially and temporally controlled drug delivery in response to tumor-specific internal or external cues. These nanocarriers are engineered to respond to physicochemical stimuli such as pH, redox potential, enzymes, hypoxia, and reactive oxygen species, or to externally applied triggers including light, heat, ultrasound, and magnetic fields. By selectively releasing therapeutic payloads at the tumor site or within resistant cancer cells, stimuli-responsive nanomedicine enhances intracellular drug accumulation, bypasses efflux mechanisms, and resensitizes tumors to chemotherapy. This review provides a comprehensive and critical analysis of the biological basis of MDR in solid tumors, the design principles of stimuli-responsive nanomedicine, and their applications in overcoming drug resistance. Current challenges and future perspectives for clinical translation are also discussed.
Keywords: multidrug resistance; stimuli-responsive nanomedicine; solid tumors; tumor microenvironment; precision drug delivery.
Multidrug resistance (MDR) remains a major challenge in the effective treatment of breast cancer, often leading to therapeutic failure, tumor recurrence, and poor clinical outcomes. Multiple mechanisms contribute to MDR, including overexpression of ATP-binding cassette (ABC) transporters, evasion of apoptosis, epithelial–mesenchymal transition (EMT), and the persistence of cancer stem cells (CSCs). In recent years, nanomedicine has emerged as a promising strategy to overcome these resistance pathways by enhancing drug delivery, improving intracellular drug accumulation, and enabling targeted and combination therapies. This review provides a comprehensive overview of nanomedicine-based approaches for overcoming MDR in breast cancer. Various nanocarrier systems, including liposomes, solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs), polymeric nanoparticles, inorganic nanocarriers, nanoemulsions, and ligand-targeted systems, are systematically discussed in terms of their design, drug delivery capabilities, and role in bypassing resistance mechanisms. Particular emphasis is placed on combination nanotherapeutic strategies, such as co-delivery of chemotherapeutic agents with natural compounds, gene modulators, or sensitizers, which have demonstrated enhanced efficacy in both in vitro and in vivo models. In addition, this review critically evaluates the limitations of current preclinical studies and highlights key challenges in clinical translation, including variability of the enhanced permeability and retention (EPR) effect, safety concerns, and large-scale manufacturing issues. 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.
Mohit Kumar, Tejaswi, Rohit Bangwal et al.· Journal of the Egyptian Nati...· 0 citations
Gastrointestinal (GI) cancers remain a major cause of cancer-related mortality worldwide, and multidrug resistance (MDR) is a critical barrier to durable therapeutic response. In GI malignancies, MDR arises from multilayered and interdependent factors, including insufficient intracellular drug accumulation, altered drug activation and metabolic detoxification, target rewiring and phenotypic plasticity, apoptosis-autophagy-mediated stress adaptation, and extrinsic protection from the tumor microenvironment, cancer stem cells, metastatic niches, and microbiome-associated mechanisms. Biomimetic delivery systems (BDSs), including cell membrane-coated nanocarriers, extracellular vesicles, and living or virus-mediated platforms, provide biological interface functions that may improve drug circulation, tumor recognition, tissue penetration, membrane interaction, and active trafficking. However, their therapeutic value in MDR GI cancers should not be judged merely by improved delivery efficiency, but by whether they address defined resistance bottlenecks and generate evidence of genuine re-sensitization in resistant disease contexts. Current evidence indicates that many BDSs remain at the level of exposure enhancement or mechanism-aligned sensitization, whereas only a limited subset has demonstrated functional restoration of treatment response in established resistant models. This review organizes current BDS strategies according to their dominant mechanistic functions: enhancing drug accumulation and intratumoral delivery, reversing cellular drug resistance, remodeling resistance-supportive tumor microenvironment, targeting cancer stem cells (CSCs) and metastatic niches, and enabling site-directed intervention using living carriers and living therapeutics. 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.
Gou Wu, Aixue Li, Yongwei Gu et al.· Drug resistance updates· 0 citations
Multidrug resistance (MDR) remains a formidable challenge in cancer therapy, often rendering conventional chemotherapeutics ineffective. Recent advances in carbohydrate polymer-based stimuli-responsive nanocarriers have opened new avenues for overcoming MDR while achieving targeted drug delivery. This narrative review highlights the unique properties of carbohydrate polymers, such as biocompatibility, biodegradability, and functional versatility, that make them ideal candidates for designing smart nanocarriers. We discuss molecular engineering strategies to develop stimuli-responsive systems capable of releasing drugs in response to tumor-specific cues like pH gradients, enzymatic activity, or external triggers such as light or temperature. A special emphasis is placed on the mechanisms by which these nanocarriers can overcome MDR, including inhibition of efflux pumps, modulation of the tumor microenvironment, and co-delivery of chemotherapeutics with gene therapies or immunomodulators. Applications in preclinical cancer models are reviewed to showcase their translational potential. This article provides a comprehensive overview of the current state-of-the-art while identifying critical knowledge gaps and emerging trends in carbohydrate polymer-based drug delivery systems for cancer therapy. By focusing on MDR and precision targeting strategies, this review offers a unique perspective that distinguishes it from existing literature.
Muhammad Liaquat Raza, Alam Shah, Habibun Nisa et al.· Nanomedicine· 0 citations
Stimuli-responsive bioengineered platforms are redefining cancer therapy by shifting therapeutic design from systemic drug exposure toward context-dependent activation within malignant tissue. These systems are engineered to sense and respond to tumor-associated or externally applied cues, including acidic pH, redox imbalance, hypoxia, enzymatic activity, reactive oxygen species, temperature variation, light, ultrasound, and magnetic fields. Across the reviewed evidence, their principal value lies not merely in drug encapsulation but in the coordinated control of localization, release, intracellular access, multimodal therapy, microenvironment modulation, and safety. The field encompasses diverse architectures, including biomacromolecular nanoparticles, hydrogels, nanogels, polymeric micelles, prodrug assemblies, lipid-based systems, mesoporous silica, metal–organic frameworks, carbon-based materials, magnetic nanocomposites, and hybrid inorganic–organic constructs. These platforms have been validated in multiple cancer models through assays of uptake, cytotoxicity, apoptosis, spheroid penetration, tumor suppression, metastasis, recurrence, immune activation, stromal remodeling, and systemic tolerability. Collectively, the evidence supports a conceptual transition from passive nanocarriers to programmable therapeutic systems capable of aligning therapeutic action with the spatial, temporal, and biological heterogeneity of tumors. However, translation remains constrained by formulation complexity, incomplete standardization, limited long-term safety and biodistribution data, insufficient penetration into protected tumor niches, and the need for clinically relevant models that capture patient-level heterogeneity. Future progress will depend on rationally simplified architectures, quantitative stimulus–response validation, scalable manufacturing, integrated safety assessment, and biomarker-guided selection of platforms matched to defined tumor microenvironments. Stimuli-responsive bioengineering therefore represents a promising, although still maturing, foundation for safer, more selective, and more mechanistically coordinated precision cancer therapy.
Hamid Omidian, Renae L. Wilson· Frontiers in Bioengineering...· 0 citations
Multidrug resistance (MDR) remains a major barrier to successful cancer chemotherapy, frequently resulting in therapeutic failure, tumor relapses, and poor clinical outcomes. Among the diverse mechanisms underlying MDR, the overexpression of ATP-binding cassette (ABC) transporters, particularly P-glycoprotein (P-gp, encoded by ABCB1) is one of the most extensively studied as it actively effluxes structurally diverse chemotherapeutic agents and reduces intracellular drug exposure below cytotoxic thresholds. In this review, we critically examine recent nanocarrier-based strategies developed to overcome P-gp-mediated resistance across major malignancies, including breast, lung, colorectal, gastric, and prostate cancers. These approaches are categorized according to their principal mechanisms of action: (i) direct functional inhibition of P-gp ATPase activity using small-molecule modulators such as quercetin, ᴅ-α-tocopheryl polyethylene glycol succinate, and tariquidar, (ii) circumvention of membrane efflux through receptor-mediated endocytosis, intracellular trafficking control, or tumor-responsive drug release, and (iii) suppression of transporter expression via co-delivery of siRNA, shRNA, or anti-miRNA payloads targeting ABCB1 regulatory pathways. We further discuss advances in nanoplatform engineering, including lipid-based nanoparticles, polymeric micelles, lipid–polymer hybrid systems, and biomimetic carriers designed to enhance tumor selectivity and intracellular retention. Preclinical evidence consistently demonstrates improved drug accumulation, restored chemosensitivity, and reduced systemic toxicity. Nevertheless, clinical translation remains constrained by tumor heterogeneity, variable biological barriers, large-scale manufacturing requirements, and regulatory complexity. Overall, nanoparticle-mediated modulation of P-gp represents a promising strategy toward precision oncology, although future success will depend on scalable design, mechanistic standardization, and biomarker-guided clinical implementation.
Andreina Quevedo-Enríquez, Katty Yi Zhang, Denisse Yajaira Enriquez et al.· Beilstein Journal of Nanotec...· 0 citations
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.
Milad Rasouli, Fatemeh Babaei, Nadia Fallahhossein et al.· Advanced Drug Delivery Revie...· 0 citations