Diabetic wounds are characterized by incomplete healing and delayed healing, resulting in a considerable global health care burden. Exosomes are lipid bilayer structures secreted by nearly all cells and express characteristic conserved proteins and parent cell-associated proteins. Exosomes harbor a diverse range of biologically active macromolecules and small molecules that can act as messengers between different cells, triggering functional changes in recipient cells and thus endowing the ability to cure various diseases, including diabetic wounds. Exosomes accelerate diabetic wound healing by regulating cellular function, inhibiting oxidative stress damage, suppressing the inflammatory response, promoting vascular regeneration, accelerating epithelial regeneration, facilitating collagen remodeling, and reducing scarring. Exosomes from different tissues or cells potentially possess functions of varying levels and can promote wound healing. For example, mesenchymal stem cell-derived exosomes (MSC-exos) have favorable potential in the field of healing due to their superior stability, permeability, biocompatibility, and immunomodulatory properties. Exosomes, which are derived from skin cellular components, can modulate inflammation and promote the regeneration of key skin cells, which in turn promotes skin healing. Therefore, this review mainly emphasizes the roles and mechanisms of exosomes from different sources, represented by MSCs and skin sources, in improving diabetic wound healing. A deeper understanding of therapeutic exosomes will yield promising candidates and perspectives for diabetic wound healing management.

Background: Hyperhomocysteinemia (HHcy) and type 2 diabetes (T2D) are recognized risk factors for non-healing wounds, yet their combined effects and underlying mechanisms remain unclear. Methods: In this study of 8406 National Health and Nutrition Examination Survey participants (1999–2004), weighted logistic regression was used to estimate odds ratios for non-healing wounds and Cox proportional hazards models were employed to assess hazard ratios for all-cause mortality. Additive and multiplicative interactions were evaluated. Nonlinear relationships used restricted cubic splines. Mediation analyses explored inflammatory marker contributions. Bulk transcriptomic and single-cell sequencing data were integrated to identify homocysteine (Hcy)-diabetic foot ulcers (DFU) hub genes, construct an Hcy risk gene scoring system, and elucidate key mechanisms by which Hcy remodels the DFU microenvironment. Results: Both T2D [odds ratio (OR): 2.42, 95% confidence interval (CI): 1.69–3.47] and HHcy (OR: 1.67, 95% CI: 1.10–2.54) independently elevated non-healing wound risk. Participants with both conditions exhibited higher odds (OR: 5.28, 95% CI: 3.20–8.70), with additive interaction (relative excess risk due to interaction: 2.83, AP: 0.54, SI: 2.95). In diabetic men, Hcy displayed a J-shaped relationship with non-healing wounds ( P for nonlinearity = 0.027), with the lowest risk around 8.9 µmol/L. In diabetic patients, inflammatory markers mediated the link, with proportions of 11.1% for red cell distribution width, 9.16% for monocyte/lymphocyte ratio, 5.28% for systemic inflammation response index, and 4.03% for neutrophil/lymphocyte ratio. Hcy drove immune-metabolic reprogramming in the DFU microenvironment by regulating key gene networks such as IL1B and MMP9, activating the MIF-CD74/CXCR4 axis to form a B cell-centric inflammatory cascade network. Both T2D and HHcy were associated with higher all-cause mortality, without joint interaction observed. Participants with a history of non-healing wounds had a higher all-cause mortality risk. Conclusions: T2D and HHcy synergistically worsen non-healing wounds, but not all-cause mortality. In diabetic males, Hcy levels displayed a J-shaped relationship with non-healing wound risk. Mechanistically, Hcy amplified systemic inflammation and drove stromal-immune crosstalk via the MIF-CD74/CXCR4 axis, reshaping the diabetic wound microenvironment.