Orally‐Delivered, Cytokine‐Engineered Extracellular Vesicles for Targeted Treatment of Inflammatory Bowel Disease

Abstract The use of orally‐administered therapeutic proteins for treatment of inflammatory bowel disease (IBD) has been limited due to the harsh gastrointestinal environment and low bioavailability that affects delivery to diseased sites. Here, a nested delivery system, termed Gal‐IL10‐EVs (C/A) that protects interleukin 10 (IL‐10) from degradation in the stomach and enables targeted delivery of IL‐10 to inflammatory macrophages infiltrating the colonic lamina propria, is reported. Extracellular vesicles (EVs) carrying IL‐10 are designed to be secreted from genetically engineered mammalian cells by a plasmid system, and EVs are subsequently modified with galactose, endowing the targeted IL‐10 delivery to inflammatory macrophages. Chitosan/alginate (C/A) hydrogel coating on Gal‐IL10‐EVs enables protection from harsh conditions in the gastrointestinal tract and favorable delivery to the colonic lumen, where the C/A hydrogel coating is removed at the diseased sites. Gal‐IL10‐EVs control the production of reactive oxygen species (ROS) and inhibit the expression of proinflammatory cytokines. In a murine model of colitis, Gal‐IL10‐EVs (C/A) alleviate IBD symptoms including inflammatory responses and disrupt colonic barriers. Taken together, Gal‐IL10‐EVs (C/A) features biocompatibility, pH‐responsive drug release, and macrophage‐targeting as a therapeutic platform for oral delivery of bioactive proteins for treating intestinal diseases.