Umbilical Cord Mesenchymal Stem Cell-Derived Extracellular Nanovesicles Alleviated Colitis via Modulating Th17/Treg Balance Through Hsa-miR-27b-3p-Mediated Suppression of PI3K/AKT/STAT3 Signaling Pathway

Background: Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract, characterized by persistent immune dysregulation. Umbilical cord mesenchymal stem cell-derived extracellular nanovesicles (MSC NVs) exhibit immunomodulatory properties, demonstrating significant therapeutic potential for clinical applications. This study sought to investigate the therapeutic effects of MSC NVs against colitis and elucidate the underlying mechanisms. Methods: MSC NVs were prepared from umbilical cord MSCs using a continuous filtration-extrusion method. The therapeutic effects of MSC NVs were assessed by tail vein injection in a murine model of DSS-induced colitis. Results: MSC NVs significantly markedly ameliorated colitis-associated symptoms, including body weight loss, colon length reduction, and elevated disease activity index scores. MSC NVs not only mitigated colitis-induced intestinal barrier impairment and inflammatory responses, but also exhibited targeted biodistribution to inflamed colonic lesions. Unexpectedly, administration of MSC-NVs via the tail vein significantly altered the gut microbial composition in colitic mice, particularly enhancing the relative abundances of beneficial commensal genera Lachnoclostridium and Dubosiella , consequently reestablishing microbial homeostasis. Moreover, MSC NVs modulated the T help (Th) 17/ regulatory T (Treg) balance within the colonic lamina propria through delivery of hsa-miR-27b-3p, which directly targeted the PIK3CA gene, thereby inhibiting PI3K/AKT/STAT3 signaling pathway activation and exerting anti-colitis effects. Conclusion: This study demonstrated that MSC NVs significantly alleviated DSS-induced colitis by modulating Th17/Treg balance in the colonic lamina propria, with hsa-miR-27b-3p identified as the key mediator through PIK3CA targeting and PI3K/AKT/STAT3 pathway inhibition. These findings highlight the therapeutic potential of filtration–extrusion-prepared MSC NVs as a safe and effective nanomedicine for IBD treatment. Keywords: colitis, umbilical cord mesenchymal stem cells, extracellular nanovesicles, Th17/Treg balance, microRNAs, PI3K/AKT/STAT3 pathway