This tutorial review discusses the convergence of drug delivery systems and PROTACs, surveys the burgeoning PROTAC delivery strategies, summarizes their design principles, clarifies their challenges, and outlooks future translational opportunities.

Inflammatory bowel diseases (IBDs) are often associated with elevated levels of reactive oxygen species (ROS) and highly dysregulated gut microbiota. In this study, we synthesized a polymer of hyaluronic acid–poly(propylene sulfide) (HA-PPS) and developed ROS-scavenging nanoparticles (HPN) that could effectively scavenge ROS. To achieve colon tissue targeting effects, the HPN nanoparticles were conjugated to the surface of modified probiotic Escherichia coli Nissle 1917 (EcN). To enhance the bacteriotherapy of EcN, we encapsulated EcN cells with a poly-norepinephrine (NE) layer that can protect EcN against environmental assaults to improve the viability of EcN in oral delivery and prolong the retention time of EcN in the intestine due to its strong mucoadhesive capability. In the dextran sulfate sodium–induced mouse colitis models, HPN-NE-EcN showed substantially enhanced prophylactic and therapeutic efficacy. Furthermore, the abundance and diversity of gut microbiota were increased after treatment with HPN-NE-EcN, contributing to the alleviation of IBDs.