Nanoengineered Drug Delivery Systems to Overcome Multidrug Resistance in Cancer

Multidrug resistance (MDR) remains one of the most critical barriers to successful cancer chemotherapy, causing relapse, metastasis, and treatment failure. MDR arises through a network of mechanisms including drug efflux transporter overexpression (e.g., Pglycoprotein/ABCB1, BCRP/ABCG2, MRPs), apoptosis evasion, enhanced DNA repair, tumor hypoxia, metabolic reprogramming, and cancer stem cell (CSC) survival. Conventional attempts to reverse MDR using efflux pump inhibitors have largely failed clinically due to systemic toxicity and pharmacokinetic drug–drug interactions. Nanoengineered drug delivery systems offer a transformative solution by altering biodistribution, improving intracellular drug accumulation, bypassing membrane efflux via endocytosis, enabling stimuli-responsive release, and supporting co-delivery of chemosensitizers, gene regulators (siRNA/shRNA), or immunomodulators. Advanced nanocarriers—including liposomes, solid lipid nanoparticles, polymeric nanoparticles, micelles, dendrimers, mesoporous silica, gold nanoparticles, and hybrid biomimetic systems—can be tuned by nanoengineering to control size, surface charge, stealth behavior, and ligand-directed targeting. Additionally, tumor microenvironment (TME) features such as acidic pH, high glutathione (GSH), hypoxia, enzyme overexpression, and abnormal vasculature can be exploited for precision release, thereby improving therapeutic index while reducing systemic toxicity. Case studies demonstrate that nanoenabled co-delivery strategies (e.g., doxorubicin + MDR1/P-gp siRNA; paclitaxel + chemosensitizers) significantly resensitize resistant tumors in preclinical models. However, clinical translation remains challenged by immunogenicity, rapid clearance, scale-up constraints, batch reproducibility, regulatory complexity, and limited patient stratification for EPR variability. This review critically analyzes MDR biology, nanoengineering frontiers, and clinically relevant design principles, and provides a roadmap for bench-to-bedside translation. Future success will depend on scalable manufacturing, strong safety evaluation, biomarker-driven patient selection, and rational combination therapies aligned with cancer resistance biology.