Aug 2026· Drug resistance updates· Vol 89, pp.
101465
· 0 citations· 191 references
Medicine
TL;DR
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.
Abstract
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.
Colon cancer (CC) is a leading cause of cancer-related mortality worldwide, and its poor prognostic outcome can be attributed to factors such as late diagnosis, tumor heterogeneity, and the failure of conventional chemotherapeutic therapies. Biomimetic nanomaterials that can mimic biological behaviors have recently generated transformative drug carriers with higher biocompatibility, evasion of the immune system, and tumor-seeking capabilities. In this review, recent progresses in biomimetic systems are summarized, such as cell membrane-coated nanoparticles, exosome-based carriers, and ligand-modified nanostructures, with a particular focus on their design paradigm and drug delivery mechanisms and the therapeutic potentiality in CC. Although preclinical investigations reveal potential response, translational barriers to clinical application remain considerable including but not limited to scalability in nanomaterial manufacturing, batch variability in produced materials, and regulatory challenges under FD/EMA regulation. Possible solutions involve cost-effective and scalable macrofluidic and automated bioreactor technologies, comprehensive protocols of exosome isolation and nanoparticle characterization, and systemic harmonization with regulatory frameworks for safety and quality at a stage earlier than the end of the process. Future directions towards combining biomimetic nanocarriers with gene-editing tools, immunotherapies, and phytochemical-based agents for synergistic effects, and the development of novel theranostic systems integrating diagnosis and treatment will be pursued. Overcoming these translational hurdles and interdisciplinary collaborations are critical for biomimetic nanomaterials to fulfil their huge potential to move colon cancer therapy closer to a safer, more effective and clinically practicable reality.
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.
Atukunda Derrick· NEWPORT INTERNATIONAL JOURNA...· 0 citations
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
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
Therapeutic resistance remains a major barrier in cancer control and is increasingly recognized as a cancer stem cell (CSC)-driven process rather than a result of residual tumor survival. CSCs sustain tumor initiation, progression, and recurrence through coordinated intrinsic and extrinsic mechanisms, including enhanced drug efflux, cellular quiescence, hypoxia tolerance, efficient DNA damage repair, metabolic adaptation, and phenotypic plasticity. These features render CSCs largely refractory to conventional chemotherapy, radiotherapy, and many molecularly targeted therapies. Although extensive efforts have focused on inhibiting CSC-associated signaling pathways, such as Wnt/β-catenin, Notch, Hedgehog, and PI3K/AKT/mTOR, clinical translation has been limited by pathway redundancy, compensatory signaling, poor tumor penetration, and systemic toxicity. Nanomaterial-based therapeutic platforms represent a promising investigational strategy with potential to address these limitations enabling multi-level intervention against CSC survival architectures. Rationally engineered nanomaterials-including metallic, carbon-based, MXene, and polymeric nanocarriers-enable multi-functional targeting of cancer stem cell resistance by enhancing intracellular delivery, modulating hypoxic niches, and inducing catalytic or photothermal cytotoxicity. These platforms integrate controlled release, ligand-mediated targeting, and microenvironment responsiveness to overcome efflux, quiescence, and repair-mediated survival pathways in CSCs. Nanomaterials bypass ATP-binding cassette transporter-mediated drug efflux, induce cell-cycle-independent cytotoxicity, remodel hypoxic niches, overwhelm DNA repair capacity, and constrain phenotypic plasticity through coordinated pathway modulation. Photothermal and catalytic nanomaterials reduce or eliminate quiescent CSC populations. while ligand-functionalized nanocarriers targeting CSC markers such as CD44, CD133, and EpCAM enhance selective delivery and intracellular drug retention. This review integrates advances in CSC biology with emerging nanomaterial-based strategies and discusses translational challenges and future directions for achieving durable cancer control through CSC-targeted nanotherapy.
K. K. Karunakar, Sowmiya Philips, Nandhini Jayaprakash· Discover Oncology· 1 citation