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Phosphatidylserine (PS) exposure increases on apoptotic colon epithelial cells during UC progression, suggesting PS\u2010targeting could enhance EcN localization. Here, EcN is engineered to surface\u2010display Annexin A5 (ANXA5), a PS\u2010binding protein, to improve inflammation targeting and colonization. Since TNF\u2010\u03b1 drives UC pathogenesis and anti\u2010TNF\u2010\u03b1 biologics face cost and safety limitations, the secretion\u2010hindering\n                    <jats:italic>lpp<\/jats:italic>\n                    gene is concurrently knocked out in ANXA5\u2010expressing EcN, creating the inflammation\u2010targeted, secretion\u2010enhanced EcN\n                    <jats:italic>\u0394lpp<\/jats:italic>\n                    ::A5. This base strain is further modified to secrete an anti\u2010TNF\u2010\u03b1 nanobody (aTN), generating EcN\n                    <jats:italic>\u0394lpp<\/jats:italic>\n                    ::A5\u2010aTN. Both engineered strains demonstrate significantly stronger colonic colonization versus wild\u2010type EcN, effectively attenuating oxidative stress\u2010mediated epithelial apoptosis, restoring mucosal barriers, improving immune\u2010microbiota balance, and alleviating murine colitis. EcN\u0394\n                    <jats:italic>lpp<\/jats:italic>\n                    ::A5\u2010aTN shows superior efficacy to EcN\u0394\n                    <jats:italic>lpp<\/jats:italic>\n                    ::A5. This study develops an engineered EcN system with enhanced targeting, colonization, and secretion. By efficiently delivering anti\u2010TNF\u2010\u03b1 nanobodies, EcN\u0394\n                    <jats:italic>lpp<\/jats:italic>\n                    ::A5\u2010aTN exhibits strong therapeutic potential for UC, overcoming limitations that hinder the clinical application of wild\u2010type EcN.\n                  <\/jats:p>","DOI":"10.1002\/advs.202512360","type":"journal-article","created":{"date-parts":[[2025,9,29]],"date-time":"2025-09-29T09:14:56Z","timestamp":1759137296000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["An Inflammation\u2010Targeting Engineered Probiotic\n                    <i>Escherichia coli<\/i>\n                    Nissle 1917 with High Anti\u2010TNF\u2010\u03b1 Nanobody Secretion Efficacy Alleviates Ulcerative Colitis"],"prefix":"10.1002","volume":"12","author":[{"given":"Siqi","family":"Hua","sequence":"first","affiliation":[{"name":"School of Biopharmacy China Pharmaceutical University  Nanjing 211198 P. 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