Programmable Biohybrid Probiotics with Long‐Term Storage Stability for Enhanced Intestinal Microbiota Regulation and Ulcerative Colitis Treatment

ABSTRACT Ulcerative colitis (UC) is a chronic inflammatory bowel disease with limited therapeutic options and high relapse rates. 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–polyphenol network (MPN) and silica‐based shell with iron‐based metal–organic framework (MIL‐101(Fe)) nanocomponents to construct a biohybrid probiotic system (Bif@FCSM(A), where “A” denotes 5‐aminosalicylic acid). This hierarchical assembly forms an oxygen‐shielding, mechanically reinforced shell, resulting in a 41‐fold improvement in aerobic storage stability and an 871‐fold enhancement in gastric survivability of the anaerobe Bifidobacterium longum . Incorporation of MIL‐101(Fe) enables high‐capacity drug loading and inflammation‐responsive disassembly via transferrin (Tf)‐mediated Fe 3 + 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–induced murine UC model, Bif@FCSM(A) markedly alleviated disease severity, suppressed pro‐inflammatory cytokines, restored mucosal immune homeostasis, and enriched short‐chain fatty acid–producing taxa. This work establishes a programmable, pathology‐responsive probiotic platform with translational potential for complex inflammatory diseases.