Transcriptomic Profiling of Skin Cells and Diabetic Wound Tissues Reveals the Pro-healing Mechanisms of an MMP-9-responsive Protein Release System

Diabetic Foot Ulcer (DFU), a severe chronic diabetes complication with low healing and high recurrence rates, is a major global health challenge. Overexpression of matrix metalloproteinase-9 (MMP-9) and the consequent MMP-9/TIMP1 (tissue inhibitor of metalloproteinase 1) imbalance delay healing by degrading the extracellular matrix, impairing granulation tissue formation, and exacerbating inflammation. Conventional therapies do not dynamically respond to fluctuating protease levels in chronic wounds. This study introduces an MMP-9-responsive protein release system (M9RR). The system enables targeted release of TIMP1 in high-MMP-9 microenvironments, thereby neutralizing excessive MMP-9 activity. RNA sequencing was performed to elucidate the mechanisms underlying the system's protective effect on skin cells (HaCaT and BJ) and its pro-healing efficacy in a diabetic wound healing mouse model.