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.