A “sticky missile”-like bioactive polyphenol-armored probiotic for targeted immunomodulation and microbiome remodeling in inflammatory bowel disease and its complication

Inflammatory bowel disease (IBD) results from dysregulated mucosal immunity and gut microbial imbalance. Probiotic therapy, while promising, is critically limited by poor gastrointestinal survival and inadequate retention at inflamed sites. Through integrated bioinformatic analyses, we identified the ATP‑gated P2X7 receptor as a central inflammatory regulator in IBD and accordingly engineered a “sticky‑missile” armored probiotic, EcN@LHP, via a one-pot supramolecular assembly. EcN@LHP is constructed via dynamic covalent complexation of the polyphenolic P2X7 inhibitor lithospermic acid (LSA) with phenylboronic‑acid‑grafted hyaluronic acid on the surface of Escherichia coli Nissle 1917. The supramolecular armor markedly improves gastric-acid resistance and mediates targeted, “missile‑like” homing to inflamed colon through electrostatic interactions, CD44 binding, and intrinsic probiotic navigation. In the inflammatory microenvironment, elevated ROS cleave boronate ester linkages, unmasking the “sticky” catechol groups for enhanced mucoadhesion and trigger controlled release of LSA. Released LSA suppresses ATP/P2X7‑driven NLRP3 inflammasome activation, reducing macrophage pyroptosis and IL‑1β/IL‑18 secretion, thereby restoring Th17/Treg and M1/M2 immune balances. In both acute and chronic colitis models, EcN@LHP shows enhanced gastric survival, prolonged colonic residence, microbiome remodeling and attenuation of colitis and colitis‑associated tumorigenesis. This bioactive polyphenol-armoring strategy presents a promising platform to endow living therapeutics with site‑specific, on‑demand pharmacology for IBD and its complications.