A Systematic Review of the Therapeutic Potential Use of Exosomes in Diabetic Foot Ulcers Healing

Abstract

Background: Diabetic foot ulcers (DFUs) a serious complication of diabetes mellitus, often leads to prolonged hospitalization, infection, and limb amputation. Their multifactorial pathogenesis includes chronic inflammation, impaired angiogenesis, oxidative stress, and defective fibroblast activity in recent years, regenerative medicine has gained attention, particularly the use of exosomes derived from adipose-derived mesenchymal stem cells (ADSCs). These exosomes carry bioactive molecules capable of modulating key processes in wound healing, including inflammation resolution, cellular proliferation, migration, and extracellular matrix remodeling. Methodology: A systematic literature review was conducted using PubMed, and Scopus to identify relevant preclinical and clinical studies published up to April, 2025. Search terms included "adipose-derived stem cells," "exosomes," "diabetic foot ulcers," and "wound healing." Studies were selected based on predefined inclusion and exclusion criteria, focusing on mechanistic insights and therapeutic outcomes of ADSC-exos in diabetic wound healing models. Results: From an initial 840 potentially eligible studies, 25 met the predefined inclusion criteria and were incorporated into the final analysis. Conclusion: ADSC-exos improve diabetic fibroblast wound healing by reducing inflammation through macrophage M2 polarization, promoting migration and proliferation of fibroblasts and keratinocytes, and supporting angiogenesis through signaling pathways such as PI3K/AKT, Wnt/β-catenin, and TGF-β/Smad. Together, these actions accelerate epithelial regeneration and granulation tissue formation. Preclinical findings consistently report enhanced healing outcomes, yet translation to human application remains limited. Challenges such as standardization of exosome isolation, dosing, delivery methods, and long-term safety must be addressed prior to clinical implementation. Nonetheless, the current findings support ADSC-Exos as a promising cell-free alternative to stem cell therapy in diabetic wound treatment and may revolutionize treatment strategies for diabetic wounds.