Proteolysis targeting chimeras (PROTAC) is an emerging targeted therapy approach, which triggers precise, robust proteasomal degradation of proteins implicated in cancer. As histone deacetylase 3 (HDAC3) and HDAC8 are involved in several biological mechanisms of breast cancer metastasis, we introduce a novel HDAC3/8 dual-degrader PROTAC drug that induces highly potent and selective degradation of both HDACs. However, wide-spread clinical use of PROTAC is limited due to instability and poor cell penetration in vivo. To enhance efficacy, we introduce a novel extracellular vesicle-based (EV) transfection platform for loading PROTAC. This approach utilizes EVs’ high biocompatibility, long circulation times, and specific targeting capabilities to enhance PROTAC cellular delivery. We compared the drug loading efficiency, EV characterization, and therapeutic functionality to conventional transfection methods. PROTAC delivery through EVs could enhance stability, biocompatibility, transportability, and targeting ability of the drug, and the novel PROTAC loading strategy fills an important gap in PROTACs functionality.
Learning Objectives:
…explore dual degrading PROTAC molecules and articulate the current limitations in PROTAC delivery and therapeutic functionality in vivo.
...obtain a comprehensive understanding of extracellular vesicles’ potential in drug delivery and the various transfection strategies for drug loading into EVs.
…learn a novel transfection method for enhanced PROTAC loading and delivery for therapeutic applications.