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Live bacterial therapeutics (LBTs) offer a promising alternative by restoring mucosal integrity, modulating immunity, and rebalancing gut microbiota; however, their clinical translation is constrained by poor storage stability, low gastrointestinal survivability, and limited therapeutic functionality. Here, we report a multilevel, modular encapsulation strategy that integrates a metal\u2013polyphenol network (MPN) and silica\u2010based shell with iron\u2010based metal\u2013organic framework (MIL\u2010101(Fe)) nanocomponents to construct a biohybrid probiotic system (Bif@FCSM(A), where \u201cA\u201d denotes 5\u2010aminosalicylic acid). This hierarchical assembly forms an oxygen\u2010shielding, mechanically reinforced shell, resulting in a 41\u2010fold improvement in aerobic storage stability and an 871\u2010fold enhancement in gastric survivability of the anaerobe\n                    <jats:italic>Bifidobacterium longum<\/jats:italic>\n                    . Incorporation of MIL\u2010101(Fe) enables high\u2010capacity drug loading and inflammation\u2010responsive disassembly via transferrin (Tf)\u2010mediated Fe\n                    <jats:sup>3<\/jats:sup>\n                    <jats:sup>+<\/jats:sup>\n                    chelation in inflamed colonic tissue, thereby achieving spatiotemporally controlled bacterial activation and drug release. Guided by UC transcriptomic signatures, this combinatorial design concurrently targets immune dysregulation and microbial imbalance. In a dextran sulfate sodium\u2013induced murine UC model, Bif@FCSM(A) markedly alleviated disease severity, suppressed pro\u2010inflammatory cytokines, restored mucosal immune homeostasis, and enriched short\u2010chain fatty acid\u2013producing taxa. This work establishes a programmable, pathology\u2010responsive probiotic platform with translational potential for complex inflammatory diseases.\n                  <\/jats:p>","DOI":"10.1002\/smll.202512736","type":"journal-article","created":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T14:36:55Z","timestamp":1770734215000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Programmable Biohybrid Probiotics with Long\u2010Term Storage Stability for Enhanced Intestinal Microbiota Regulation and Ulcerative Colitis Treatment"],"prefix":"10.1002","volume":"22","author":[{"given":"Jiani","family":"Jiang","sequence":"first","affiliation":[{"name":"Guangdong Engineering Research Center of Low\u2010Carbon Synthetic Biotechnology State Key Laboratory of Pulp and Paper Engineering School of Biology and Biological Engineering South China University of Technology  Guangzhou P. R. 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