Integrating Proteolysis-Targeting Chimeras (PROTACs) with Delivery Systems for More Efficient and Precise Targeted Protein Degradation.

Targeted protein degradation (TPD) using the proteolysis-targeting chimeras (PROTACs) is emerging as a revolutionary technology, offering a potential strategy for cancer treatment by inducing the degradation of overexpressed oncogenic proteins in tumors. PROTACs function by recruiting E3 ligases and utilizing the ubiquitin-proteasome pathway (UPS) to catalyze the degradation of target oncogenic proteins. Compared to traditional small molecules inhibitors, PROTACs exhibit enhanced selectivity, the ability to overcome drug resistance, and target proteins traditionally deemed "undruggable". However, the poor water solubility and low cellular permeability of PROTACs significantly limit their pharmacokinetic properties, while potential systemic toxicity may hinder their clinical application. To address these limitations, strategies that integrate PROTACs with drug delivery systems are gaining attention. This review summarizes the latest advancements in various delivery strategies to enhance the in vivo degradation efficacy and reduce off-target effects of PROTACs, including the prototype delivery of PROTACs using nanoparticles, covalent modification-based prodrug strategies, innovative multi-headed PROTACs designs, and microneedle delivery systems, while discussing their design principles and associated challenges. The combination of potent PROTACs with multifunctional delivery systems holds promise for accelerating clinical translation and improving therapeutic efficacy in cancer treatment.