Smad7-based biologic targets neutrophil NETosis in diabetic wound models

Summary: Abstract Body: Neutrophils are crucial in the early phase of wound healing but can impair healing when excessive neutrophil extracellular traps (NETs) are formed. In diabetes, neutrophils are primed for NETosis, a process that exacerbates tissue damage and chronic inflammation, hindering wound healing. This study explored the mechanisms of diabetic wound healing defects and evaluated a Smad7-based therapeutic intervention. We engineered Tat-PYC-Smad7, a biologic comprising the PY motif and C-terminal domain of human Smad7 fused with a cell-penetrating Tat tag for topical application. Tat-PYC-Smad7 accelerated wound closure and improved extracellular matrix (ECM) remodeling in diabetic mouse and pig models. RNA sequencing revealed that the top pathways targeted by Tat-PYC-Smad7 are related to neutrophil functions and NET formation. Mechanistic studies revealed that Tat-PYC-Smad7 inhibits histone 3 citrullination, a critical step in NETosis, by directly binding to and suppressing myeloperoxidase (MPO) activity. This suppression reduced elastase release and tissue damage while promoting keratinocyte survival and ECM deposition. These findings highlight the pivotal role of NETosis in diabetic wound pathology and the potential of Smad7-based biologic for therapeutic intervention. Yao Ke^{1, 2}, Ben-Zheng Li³, Sean R Collins⁴, Christian D Young¹, Xiao-Jing Wang^{1, 2} 1. Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States. 2. University of California Davis School of Medicine, Sacramento, CA, United States. 3. Department of Physiology and Biophysics, University of Colorado Anschutz Medical Campus, Aurora, CO, United States. 4. Department of Microbiology & Molecular Genetics, University of California Davis School of Medicine, Sacramento, CA, United States. Stem Cell Biology, Tissue Regeneration and Wound Healing