Remodeling the Physicochemical and Pharmacokinetic Properties of PROTAC via Lipid Nanodisks for Cancer Therapy

Abstract Proteolysis targeting chimera (PROTAC), as an emerging approach for target protein degradation based on the intracellular ubiquitin‐protease system, is characterized by catalytic and reusability over traditional inhibitors. However, PROTACs are fraught with pharmacokinetic dangers due to poor water solubility and membrane permeability, further posing a huge challenge to the clinical potential. Herein, a nanodelivery system is developed that is elaborately decorated with prodrugs to improve the physicochemical properties and therapeutic efficacy of PROTAC. The nanodelivery, lipid nanodisk (LND), is readily assembled from three commercially available phospholipids, and shows high stability and long circulation time in vivo. The lipid‐derived prodrug realizes prolonged retention and precise release of PROTACs at tumor sites under the endogenous stimulus. Collectively, the LND loaded with MZ1 prodrug (LND‐MZ1) presents enhanced biocompatibility, improves intracellular accumulation, and superior tumor penetration capacity, enabling more potent and targeted PROTAC therapy with enhanced specificity in vivo. LND‐MZ1 shows a more significant anti‐tumor effect in the xenograft tumor model, even at a one‐tenth dose of the parent PROTACs under the same therapeutic schedule. Overall, the LND‐based nanomedicine paves the way for remodeling the physicochemical and pharmacokinetic properties of various drugs to expand the therapeutic scope.