Stem Cell-Derived Exosomes for Diabetic Wound Healing: Mechanisms, Nano-Delivery Systems, and Translational Perspectives

Diabetic wounds remain chronically non-healing due to impaired angiogenesis, persistent inflammation, and defective extracellular matrix remodelling. In recent years, stem cell-derived exosomes have emerged as a potent cell-free regenerative strategy capable of recapitulating the therapeutic benefits of mesenchymal stem cells while avoiding risks associated with direct cell transplantation. This review critically evaluates the preclinical evidence supporting the use of exosomes derived from adipose tissue, bone marrow, umbilical cord, and induced pluripotent stem cells for diabetic wound repair. These exosomes deliver bioactive cargos such as microRNAs, proteins, lipids, and cytokines that modulate key signalling pathways, including Phosphatidylinositol 3-kinase/Protein kinase (PI3K/Akt), Nuclear factor kappa B (NF-κB), Mitogen-activated protein kinase (MAPK), Transforming growth factor-beta (TGF-β/Smad), and Hypoxia inducible factor-1α/Vascular endothelial growth factor (HIF-1α/VEGF), thereby promoting angiogenesis, accelerating fibroblast and keratinocyte proliferation, facilitating re-epithelialization, and restoring immune balance through M2 macrophage polarization. A central focus of this review is the recent advances in exosome-based delivery systems, including hydrogels, microneedles, 3D scaffolds, and decellularized extracellular matrix composites, which significantly enhance exosome stability, retention, and targeted release at wound sites. Comparative insights between stem cell therapy and exosome therapy highlight the superior safety, scalability, and regulatory advantages of exosome-based approaches. We also summarize progress in exosome engineering, manufacturing, quality control, and ongoing clinical investigations, along with challenges related to standardization, dosage, and translational readiness. Collectively, this review provides a comprehensive mechanistic and translational framework that positions stem cell-derived exosomes as a next-generation, cell-free regenerative strategy with the potential to overcome current therapeutic limitations and redefine clinical management of diabetic wound healing.