Decellularized small intestinal hydrogel-encapsulated BMSCs attenuate dextran sulfate sodium-induced colitis in mice <i>via</i> immunomodulation and tissue repair

The treatment of inflammatory bowel disease (IBD) urgently requires effective and safe strategies, and mesenchymal stem cell (MSC)-based therapy has emerged as a research focus due to its immunomodulatory and tissue-repairing capabilities. To enhance the therapeutic efficacy of MSCs, this study developed a decellularized small intestinal (dSI) hydrogel delivery system to encapsulate rat bone marrow-derived MSCs (rBMSCs) for targeted rectal administration to colitis lesions in mice. Results demonstrated that the dSI hydrogel significantly improved the <i>in vivo</i> survival rate of rBMSCs and effectively alleviated dextran sulfate sodium (DSS)-induced colitis symptoms. The dSI hydrogel significantly improved rBMSCs survival <i>in vivo</i> and ameliorated DSS-induced colitis by: suppression of pro-inflammatory cytokines and myeloperoxidase (MPO) expression; restoration of intestinal barrier function and promotion of mucosal regeneration. The dSI hydrogel outperformed conventional PLGA-PEG-PLGA hydrogels in tissue repair due to its superior bioactivity, biocompatibility, biodegradability, and mechanical properties, while its low immunogenicity ensured therapeutic safety. The combined treatment mitigated inflammation, oxidative stress, and tissue damage through multi-target synergistic effects, offering a novel therapeutic approach for IBD. Future studies should further investigate the interaction mechanisms between dSI hydrogel and rBMSCs, optimize dosing regimens, and employ single-cell RNA sequencing to elucidate MSC-mediated immunomodulation in the gut microenvironment. This study provides experimental evidence for the clinical translation of dSI hydrogel-based MSC therapy, highlighting its potential as a promising strategy for IBD treatment.