Self-Assembled Nanocomplexes of Oligomerized Catechins and Deoxyribonuclease-I for Synergistically Enhancing Diabetic Wound Healing

Abstract

Diabetic ulcers (DUs), a severe complication of diabetes, are characterized by impaired wound healing and contribute significantly to morbidity and mortality. A key pathological driver is the persistent accumulation of neutrophil extracellular traps (NETs), which extend inflammation and tissue damage; however, appropriate therapeutic strategies to resolve NETs remain underdeveloped. We engineered a self-assembled nanocomplex, O/DNase-I, through structural and functional integration of oligomerized epigallocatechin gallate (OEGCG) and deoxyribonuclease-I (DNase-I). Its functionality was systematically evaluated in vitro and in a diabetic murine wound model using molecular and histological analyses. The O/DNase-I nanocomplex simultaneously eliminates existing NETs via DNase-I-mediated DNA hydrolysis and suppresses further NET formation through OEGCG. This synergistic action robustly cleared NETs, mitigated pro-inflammatory signaling, and critically, promoted a reparative immune microenvironment by driving M2 macrophage polarization, ultimately accelerating diabetic wound closure in vivo. This study not only validates O/DNase-I as a potent therapeutic approach for diabetic wound management but also establishes a novel supramolecular strategy for targeting dysregulated inflammation, with broad potential applications in other NET-associated pathologies.