Immunomodulatory Properties of Mesenchymal Stem Cells and Their Extracellular Vesicles: Potential Clinical Applications in Autoimmune Diseases.

Mesenchymal stem cells (MSCs)/mesenchymal stromal cells and their extracellular vesicles (EVs), particularly exosomes, have emerged as therapeutic candidates in regenerative medicine due to their multipotency, low immunogenicity, and extensive immunomodulatory properties. This narrative review provides a narrative synthesis of MSC- and MSC-EV-mediated immunomodulation and its translational potential across four major autoimmune diseases: multiple sclerosis (MS), type 1 diabetes mellitus (T1D), systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA). Mechanistically, MSCs regulate both innate and adaptive immune cell populations, modulate pro- and anti-inflammatory cytokine secretion, downregulate pro-inflammatory Th1/Th17 responses, and promote regulatory phenotypes, including regulatory T cells, regulatory B cells, and M2-polarized macrophages. Preclinical and clinical investigations suggest therapeutic potential across these diseases; however, much of the clinical evidence derives from small, early-phase, and frequently uncontrolled studies with limited follow-up, and safety outcomes vary according to MSC source, manufacturing process, dose, route of administration, and clinical indication. In these studies, the absence of serious adverse events does not constitute definitive evidence of long-term safety. Clinical studies have reported reductions in disease activity scores and inflammatory biomarkers, as well as improvements in disease-specific functional outcomes; however, these findings should be regarded as preliminary evidence of therapeutic potential rather than established efficacy across autoimmune diseases. Nonetheless, clinical translation remains hindered by manufacturing heterogeneity, variability in dosing, routes of administration, and treatment protocols, as well as challenges related to allogeneic immunogenicity and MSC-EV standardization. Overcoming these barriers will require standardized manufacturing and characterization protocols, alongside further investigation into the integration of MSC- and MSC-EV-based therapies within multimodal, personalized, and patient-tailored treatment frameworks.