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

Abstract

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.