Mesenchymal stromal cell-free therapies for the treatment of inflammatory bowel disease.

Cell-free therapies derived from the mesenchymal stromal cell (MSC) secretome and its extracellular vesicles (EVs) are emerging as a new class of biologics for inflammatory bowel disease (IBD). These acellular formulations capture the immunomodulatory and regenerative effects of MSCs while avoiding the safety, scalability, and regulatory limitations associated with live-cell products. In preclinical models of ulcerative colitis (UC), both whole secretome preparations and isolated EVs have shown consistent therapeutic effects in preclinical models, suggesting reduced inflammation and enhanced mucosal healing through intravenous, intraperitoneal, intracolonic, or intragastric delivery routes. Local administration, particularly intracolonic and intragastric, has yielded the most pronounced outcomes by targeting the affected intestinal tissue directly. Despite these promising preclinical findings, clinical translation remains limited, with only five trials initiated to date. Major challenges include product standardization, potency assessment, and large-scale manufacturing. This review highlights recent advances and persisting bottlenecks in MSC-derived cell-free approaches for IBD, outlining the technological and regulatory milestones required to achieve their clinical implementation.