Emerging Strategies in Smart Nano-PROTAC for Stimuli-Responsive Protein Degradation and Precision Cancer Therapy

Proteolysis-targeting chimeras (PROTACs) have emerged as a promising therapeutic strategy for targeted protein degradation. They offer several advantages over traditional small-molecule inhibitors, including catalytic efficiency, high specificity, and the ability to degrade previously undruggable targets. To date, the most advanced therapeutics of PROTAC, ARV-471, and CC-94676 have progressed into Phase III clinical trials, marking a significant milestone in the clinical translation of targeted protein degradation strategies. However, despite their success in clinical trials, current PROTACs face challenges such as poor cell permeability, systemic off-target effects, and the “hook effect”, which hinder broader clinical translation. To address these limitations, stimulus-responsive nanoparticle-based PROTACs (nano-PROTACs) have been developed to enable spatiotemporally controlled protein degradation. These advances exploit endogenous or exogenous stimuli (such as redox status, enzymes, light, and ultrasound) to achieve precise activation, thereby enhancing therapeutic efficacy while minimizing systemic toxicity. This review highlights recent advances in stimulus-responsive nano-PROTACs, with particular emphasis on the design of novel ligands and linkers. These emerging smart nano-PROTAC strategies enhance specificity and controllability, paving the way for next-generation degraders with improved pharmacological properties.