Efficient healing of diabetic wounds by MSC-EV-7A composite hydrogel via suppression of inflammation and enhancement of angiogenesis

Diabetes mellitus (DM) is characterized by prolonged hyperglycemia, impaired vascularization, and serious complications, such as blindness and chronic diabetic wounds. About 25% of patients with DM are estimated to encounter impaired healing of diabetic wounds, often leading to lower limb amputation. Multiple factors are attributed to the non-healing of diabetic wounds, including hyperglycaemia, chronic inflammation, and impaired angiogenesis. It is imperative to develop more efficient treatment strategies to tackle healing difficulties in diabetic wounds. Mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) are promising for diabetic wound healing considering their anti-inflammatory, pro-angiogenic and pro-proliferative activities. A histone deacetylase 7 (HDAC7)-derived 7-amino-acid peptide (7A) was shown to be highly effective for angiogenesis. However, it has never been investigated whether MSC-EVs are synergistic with 7A for the healing of diabetic wounds. Herein, we propose that MSC-EVs can be combined with 7A to greatly promote diabetic wound healing. The combination of EVs and 7A significantly improved the migration and proliferation of skin fibroblasts. Moreover, EVs alone significantly suppressed LPS-induced inflammation in macrophages, and notably, the combination treatment showed an even better suppression effect. Importantly, the in vivo study revealed that the combination therapy consisting of EVs and 7A in an alginate hydrogel was more efficient for the healing of diabetic wounds in rats than monotherapy using either EV or 7A hydrogels. The underlying mechanisms include suppression of inflammation, improvement of skin cell proliferation and migration, and enhanced collagen fiber disposition and angiogenesis in wounds. In summary, the MSC-EV-7A hydrogel potentially constitutes a novel therapy for efficient healing of chronic diabetic wounds.