Smad7-based biologic targeting epidermis and stroma promotes healing of diabetic wounds in mice and pigs

Abstract This study aimed to identify novel mechanisms of diabetic wound healing defects and test a therapeutic intervention using diabetic mouse and pig models. We found Smad7 transgene expression in mouse epidermis promoted wound healing in diabetic mice. To isolate effects of Smad7 on wounds, we created a Smad7-based biologic (Tat-PYC-Smad7) that penetrated cells of the wound. Topical Tat-PYC-Smad7 treatment to diabetic pig and mouse wounds accelerated healing compared to vehicle controls. Tat-PYC-Smad7-treated wounds showed reduced TGFβ/NFκB signaling, faster re-epithelialization and better extracellular matrix remodeling. Tat-PYC-Smad7 also attenuated neutrophil NETosis, potentially acting through reductions in MPO enzymatic activity and MPO nuclear entry, consequently reducing chromatin decondensation and the release of NET components. Our study revealed that Tat-PYC-Smad7 promoted diabetic wound healing by targeting keratinocytes and neutrophils, providing insight into mechanisms of diabetic wound healing defects targetable by Smad7-based therapy.