Engineered resveratrol nanoantioxidants: intestinal targeted oral delivery system of mesalazine for inflammatory bowel disease via spatiotemporal-ecological regulation

Abstract Inflammatory bowel disease (IBD) is a life-threatening condition associated with excessive reactive oxygen species (ROS), chronic mucosal inflammation, and gut microbiota dysbiosis. The therapeutic potential of resveratrol (Rv) and mesalazine (Mz) is limited by poor solubility, nonspecific distribution, and low delivery efficiency. To overcome these challenges, we introduce an integrated nanotherapeutic approach where we modify hyaluronic acid (HA) onto the surface of Mz-encapsulated mesoporous Rv-crosslinked polyphosphazene nanobowl (named PHRv@Mz@HA), for multitarget therapy in IBD. Benefiting from the negatively charged surface of HA coating and abundant phenolic hydroxyl groups in PHRv@Mz@HA, it allows for prolonged retention to the gastrointestinal tract and targeted accumulation of the nanomedication to the positively charged inflamed colon regions through electrostatic interactions and bioadhesion. Subsequently, PHRv@Mz@HA specifically binds to CD44-overexpressed inflammatory cells (especially macrophages), thus significantly alleviating oxidative stress and inflammation at IBD lesions. Specifically, mechanistic studies revealed that PHRv@Mz@HA exerted its effects through activating Nrf2/HO-1 signaling pathway for ROS scavenging, while suppressing the inflammatory response by down-regulating TLR4/NF-κB signaling pathway. In the mice models of dextran sulfate sodium- and trinitrobenzenesulfonic acid-induced acute colitis demonstrated that oral administration of PHRv@Mz@HA achieved outperformed therapeutic effects compared with standard drug Mz, as evidenced by elimination of oxidative stress, decreased colonic and systemic inflammation, repaired intestinal barrier, and restored gut microbiota balance. By integrating targeted delivery with bioresponsive release of natural medicine, this work offered a safe and effective intervention for IBD treatment. Graphical Abstract