Folate‐PEG‐PROTAC Micelles for Enhancing Tumor‐Specific Targeting Proteolysis In Vivo

Abstract Proteolysis targeting chimeras (PROTACs) technology is rapidly developed as a novel and selective medicinal strategy for the degradation of cellular proteins in cancer therapy. However, the applications of PROTACs as heterobifunctional molecules are largely limited by high molecular weight, low bioavailability, poor permeability, insufficient targeting, and low efficacy in vivo. Herein, self‐assembling micelles of FA‐PEG‐PROTAC are designed for cancer cell selective targeting and reductive‐response proteolysis in tumor‐bearing mice. FA‐PEG‐PROTAC is prepared by conjugating folic acid (FA)‐PEG with EGFR‐targeting PROTAC via a disulfide bond. The FA‐PEG‐PROTAC micelles, formed by self‐assembling, are demonstrated to significantly improve tumor targeting efficacy and exhibit excellent anti‐tumor efficacy in the mouse xenograft model compared to the traditional PROTACs. The strategy of applying self‐assembled FA‐PEG‐PROTAC micelles in tumor therapy can not only improve targeted proteolysis efficiency but also broaden applications in the development of PROTAC‐based drugs.