Orally administered biomimetic nanovesicles engineered with FGF2 orchestrate mucosal healing and microbiome remodeling in inflammatory bowel disease.

Inflammatory bowel disease (IBD) is characterized by chronic intestinal inflammation and profound microbial dysbiosis, presenting significant therapeutic challenges. While fibroblast growth factor 2 (FGF2) possesses potent regenerative capabilities, its oral administration is severely hindered by rapid gastrointestinal degradation. To overcome these delivery barriers, this study investigates a novel, targeted therapeutic strategy utilizing nanoscale outer membrane vesicles (OMV/FGF2) naturally secreted during the normal growth of FGF2-engineered Gram-negative bacteria. The isolated OMV/FGF2 (120.1 nm, -13.7 mV) maintained robust structural integrity in simulated gastric fluid and demonstrated highly favorable cytocompatibility. In a dextran sulfate sodium (DSS)-induced murine colitis model, orally administered OMV/FGF2 significantly attenuated disease severity, mitigating weight loss and colon shortening. Mechanistically, OMV/FGF2 actively restored the intestinal physicochemical barrier by upregulating tight junction proteins (Occludin, ZO-1) and promoting mucus hypersecretion. Furthermore, 16S rRNA analysis revealed that OMV/FGF2 reversed microbial dysbiosis, enhancing α-diversity and enriching beneficial commensals (e.g., Bacteroides, Lactobacillus) while suppressing pathogenic populations. Ultimately, OMV/FGF2 ameliorates intestinal inflammation through a synergistic dual mechanism of fortifying the epithelial barrier and remodeling the gut microbiome. This engineered nanoplatform provides a promising, orally bioavailable therapy for IBD.