Mucosal Colonized Engineered Nissle 1917 for Targeted Gut Delivery and Restored Microbiota Homeostasis in Inflammatory Bowel Disease

ABSTRACT Inflammatory bowel disease (IBD) is a serious health problem with an increasing disease burden. Oral probiotics are a potential treatment for IBD. However, the limited colonization and lack of sustained activity in the inflamed colon are challenging. In this research, mucosal colonized engineered Nissle 1917 ( EcN ) was designed for targeted gut delivery and restored microbiota homeostasis in IBD. 2‐iminothiolane thiolation was modified on the surface of EcN , thus the employed disulfide bonds can targeted bind with intestinal mucus layer, enhancing EcN activity and retention in the inflamed colon so that the gut microbiota homeostasis can be restored effectively. Further, we developed a probiotic‐based therapeutic platform to load Ononin onto EcN via manganese mineralization (OME). Oral OME can colonize the intestine and deliver drugs to the inflamed colon, exhibiting synergistic targeted drug‐therapeutic effects and restoring macrobiotic homeostasis. Further mechanism study showed that OME ameliorates DSS‐induced intestinal inflammation by upregulating Eubacterium coprostanoligenes, which secretes methylmalonyl‐CoA mutase to modulate intestinal T cell proportions and functional polarization, ultimately restoring immune homeostasis. This research highlighted the potential of mucosal colonized engineered EcN to restore microbiota homeostasis and targeted delivery of drugs, offering a promising strategy for clinical applications.