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 re
sensitizes 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.