MMP-9-responsive bFGF/FGF21 patch synergistically piloting the immune remodeling and regeneration of diabetic wounds

Diabetic chronic wounds are marked by a dysregulated immune microenvironment, impaired angiogenesis, and delayed granulation tissue formation, all of which limit the wound recovery under conventional therapies. Effective restoration of the normal healing dynamics, therefore, required not only targeted stimulation of tissue repair but, more critically, reprogramming of the dysregulated immune reaction. To address this, we developed a dual-layer electrospun patch that integrates immune regulation and regenerative promotion through the spatiotemporally controlled release of fibroblast growth factor 21 (FGF21) and basic fibroblast growth factor (bFGF). The poly(lactic acid)/triglycerol monostearate-based patch exhibited MMP-9-responsive and sustained release of FGF21 and bFGF over 14 days. In a type 2 diabetic mouse model, FGF21 induced an M1 to M2 polarization in the cutaneous wounds and regulated the inflammation-related factors to provide a reparative microenvironment, under which bFGF more effectively enhanced angiogenesis and dermal matrix remodeling. Therefore, the bFGF/FGF21 patch significantly accelerated wound closure, re-epithelialization, collagen deposition, and tissue regeneration. This strategy presents a promising approach for treating chronic diabetic wounds.