Review of Stimuli-Responsive Polymeric Prodrug Nanomaterials for Cancer Therapy

Off-target effects of conventional chemotherapeutics often cause severe toxicities, posing a persistent clinical obstacle in cancer therapy. Nanodelivery systems can enhance tumor accumulation via the enhanced permeability and retention effect, yet reconciling systemic stability with rapid and site-specific drug release remains a longstanding challenge. Stimuli-responsive polymeric prodrugs, which integrate tumor microenvironment-responsive linkages with polymer-drug conjugation strategies, offer a promising solution by combining improved circulatory stability with selective activation at tumor sites. In this review, we summarize recent advances in the design of stimuli-responsive polymeric prodrugs according to characteristic tumor microenvironmental features, discuss their representative applications and mechanistic advantages, and outline the current limitations, translational challenges, and future directions in this field.