Stimuli-Responsive Nanomedicine for Overcoming Multidrug Resistance in Solid Tumors

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.