NANOTECHNOLOGY-DRIVEN APPROACHES TO OVERCOME CHEMORESISTANCE IN CANCER THERAPY

Abstract

Chemoresistance remains a major obstacle to effective cancer therapy, accounting for over 90% of therapeutic failures in advanced malignancies. It arises through multidimensional mechanisms, including the over expression of ATP-binding cassette (ABC) efflux transporters (P-gp, MRPs, and BCRP), enhanced DNA repair, anti-apoptotic signaling, epithelial–mesenchymal transition (EMT), cancer stem cell (CSC) persistence, and a hostile tumor microenvironment (TME) characterized by hypoxia, acidosis, and dense stroma. Conventional chemotherapy fails to address these complexities owing to poor selectivity, toxicity, and limited tumor penetration. Nanotechnology offers a transformative approach that enables targeted and controlled drug delivery through carriers, such as liposomes, polymeric nanoparticles, dendrimers, mesoporous silica nanoparticles, and gold nanostructures. These systems leverage passive (EPR effect) and active targeting mechanisms to bypass efflux pumps, co-deliver therapeutics with P-gp inhibitors, siRNA, or CSC-targeting ligands, and modulate the TME via stimuli-responsive release (pH, redox, enzymes, or light). Preclinical and clinical investigations-such as with Doxil®, Abraxane®, and CRLX101 have demonstrated enhanced drug accumulation, restored chemosensitivity, and reduced systemic toxicity. Despite promising outcomes, challenges persist in terms of EPR variability, large-scale reproducibility, immune clearance, and long-term safety. Emerging innovations,such as biomimetic and exosome-mimetic nanocarriers, AI-assisted nanodesign, CRISPR-loaded nanoparticles, and precision diagnostics,hold promise for  personalizing and optimizing future cancer nanotherapeutics. Collectively, nanotechnology-driven strategies hold immense potential for overcoming chemoresistance, improving clinical outcomes, and redefining the landscape of cancer treatment through integrated, intelligent, and patient-tailored approaches.