Prodrug Strategy for PROTACs: High Efficiency and Low Toxicity.

At present, PROTACs have garnered significant attention as a burgeoning therapeutic approach. Relying on endogenous E3 ubiquitin ligases, PROTACs achieve the catalytic degradation of target proteins through a cyclic catalytic mechanism. Its event-driven pharmacology has resolved the problem of "undruggable" targets in diseases, such as cancers, greatly expanding the field of drug development. Nevertheless, the clinical implementation of PROTACs is constrained by their systemic toxicity and suboptimal bioavailability. In response, PROTAC prodrugs have emerged as a strategy to enable spatiotemporally controlled protein degradation in specific target tissues. This approach leverages diverse stimuliincluding light, enzymes, and immune system componentsto achieve precise activation and localized action. Meanwhile, to address the issues of druggability, some systems for PROTAC delivery have also been developed, such as polymers, conjugates, albumin, and liposomes. Overall, this review discusses the activation methods and optimization strategies of PROTACs.