Liraglutide-loaded PLGA/gelatin electrospun nanofibrous mats promote angiogenesis to accelerate diabetic wound healing via the modulation of miR-29b-3p

Diabetic wounds remain a serious clinical challenge whereas current therapies have limited effects on reducing the high disability and morbidity. Impaired vascularization is closely associated with delayed healing of diabetic wounds and liraglutide (Lira), a GLP-1R receptor agonist, has been reported to promote the angiogenic ability of endothelial cells. However, its application is hindered owing to the unsustainable drug concentration. In this study, we prepared a poly (lactic-co-glycolic acid)/gelatin (PLGA/Gel) nanofibrous mat scaffold to sustain the release of Lira for skin tissue engineering through 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide/N-hydroxy sulfosuccinimide (EDC/NHS), a green cross-linking-graft integration method. The incorporation of Lira into PLGA/Gel increased the pore size, hydrophilicity, elasticity and degradation properties of nanofibrous mats, which were advantageous to wound healing. In addition, the effects on diabetic wound healing, vascularization and its underlying mechanism were evaluated. The results revealed that PLGA/Gel/Lira remarkably improved the healing efficiency of diabetic dermal wounds characterized by shortened wound closure time, increased blood vessel density, and elevated collagen deposition and alignment. In vitro, Lira reversed the inhibitory effects on proliferation, migration, tube differentiation, and VEGF secretion of endothelial cells induced by high glucose (HG). As for the underlying mechanism, Lira specifically decreased the level of miR-29b-3p, targeting the AKT/GSK-3β/β-catenin pathway to regulate the biological function of endothelial cells. In conclusion, for the first time this study combined PLGA/Gel with Lira to take advantage of their synergistic effects to promote vascularization, a promising strategy to accelerate diabetic wound repair.