Photo-Assisted NanoPROTACs for Targeted Cancer Therapy

Proteolysis targeting chimeras (PROTACs) have evolved into a revolutionary therapeutic strategy that recruit the ubiquitin-proteasome pathway to selectively degrade proteins of interest (POIs). Despite their potential to expand the druggable landscape, conventional PROTACs are often hindered by challenges such as poor membrane permeability, systemic off-target effects, and the hook effect. Therefore, photo-assisted nano-proteolysis targeting chimeras (nanoPROTACs) have recently emerged, combining nanotechnology strategy with photo-assisted control to addresses the inherent constraints of conventional PROTACs. Such integrated platforms offer multifaceted advantages by promoting targeted tissue accumulation, enhancing intracellular delivery, allowing spatiotemporally precise drug activation, and facilitating synergistic effects when combined with other therapies. This review comprehensively outlines the design principles, operational mechanisms, and recent progress in photo-assisted nanoPROTAC development. By permitting spatiotemporally controlled protein degradation and enabling combinatory regimens with photo therapies, these systems offer a powerful and tunable strategy for precision oncology. This review provides the first comprehensive overview of photo-assisted nanoPROTACs. Our discussion aims to provide insightful perspectives on this advancing field and inspire further innovation toward stimuli-responsive therapeutic platforms.