Mesenchymal Stromal Cell-Derived Secretome for Diabetic Foot Ulcers: Therapeutic Potential, Challenges in Clinical Translation, and Future Directions

Background: Diabetic foot ulcers (DFUs) represent one of the most challenging chronic complications of diabetes mellitus, developing in approximately 15 to 25% of affected individuals over their lifetime and imposing a substantial burden on healthcare systems worldwide. Even with coordinated, multidisciplinary wound management strategies, a substantial proportion of these ulcers fail to heal in a timely manner, predisposing patients to secondary infection, lower-limb amputation, and elevated mortality risk. Mesenchymal stromal cells (MSCs) have long been investigated as a regenerative treatment option given their reparative capacity; however, translating live-cell therapy into routine practice has been hindered by limited post-transplantation cell viability, inefficient tissue engraftment, and the practical difficulties of large-scale cell manufacturing. As an alternative, attention has shifted toward the MSC-derived secretome a complex mixture of extracellular vesicles, cytokines, chemokines, trophic factors, and microRNAs which appears to preserve much of the parent cells regenerative and immune-modulating activity without the drawbacks associated with administering live cells. Methods: In this review, we examine the biological composition and mechanistic actions of the MSC secretome as they relate to DFU repair, focusing specifically on strategies for topical application. Results: Evidence from preclinical diabetic wound models points to accelerated wound closure, stimulation of new blood vessel formation, remodeling of the extracellular matrix, and dampening of persistent inflammatory activity following secretome treatment. Findings from early clinical trials have likewise been encouraging, with rates of complete wound closure ranging from 62 to 100% across two limited studies enrolling between 10 and 110 participants, with outcomes varying according to the cellular origin of the secretome, the route by which it was delivered, and differences in study design. Several barriers still limit clinical adoption. GMP-compliant production protocols have not been harmonized across manufacturers. Batches vary from one production run to the next. No validated assay yet exists to measure biological potency. Long-term safety data remain limited, and questions about the appropriate dose are still unresolved. Looking ahead, engineered or modified secretome formulations, combination therapies, and smart wound-monitoring devices may help improve outcomes further. Conclusion: Current evidence supports the MSC secretome as a promising, cell-free option for DFU management. Its place in standard clinical care will depend on large, multicenter randomized controlled trials and on establishing consistent, standardized manufacturing practices.