Hyaluronic acid-modified and glutathione-responsive degradable dendritic mesoporous organosilicone nanoparticles for augmenting targetability and degradation potency of PROTAC

Proteolysis targeting chimera (PROTAC) technology had aroused considerable research interest in the past few decades. However, PROTAC technology still suffers some limitations such as unfavorable aqueous solubility, limited cell membrane permeability, poor tissue selectivity and adverse side effects. To advance its clinical translation, herein, a hyaluronic acid (HA)-encapsulated and GSH-responsive degradable dendritic mesoporous organosilicone nanoparticles was constructed as novel nanocarrier for enhanced delivery and controllable releasing of PROTAC within cancer cells. As a proof of concept, PROTAC ARV-771 is chosen and the DMONs-NH 2 @ARV-771@HA nanocomplex is prepared by step-by-step loading of ARV-771 and HA. The results showed that the DMONs-NH 2 @HA can specifically and efficiently transport cargo molecules into the tumor cells through CD44 receptor-mediated endocytosis. Moreover, the redox reaction with glutathione causes the breakup of DMONs-NH 2 and subsequent controllable release of ARV-771, enabling degradation of target protein BRD4 and selective therapy within tumor cells. The DMONs-NH 2 @HA nanoparticles only provide a novel delivery system for PROTAC but also may facilitate the clinical application of PROTAC in the near future.