Bioactive Nanocomposite-Mediated Macrophage Metabolic Shift Orchestrates Pro-Regenerative Healing in the Diabetic Wound Microenvironment

Introduction: Chronic diabetic wounds suffer from persistent oxidative stress, unresolved inflammation, and impaired neovascularization, with limited effective therapies. Methods: We developed a biomimetic nanocomposite (PEG-HS/TiO2) combining antioxidant TiO2 with sustained-release honeysuckle. In vitro, we evaluated ROS scavenging, cellular senescence, VEGF expression, and macrophage polarization. In vivo, we assessed wound closure, neovascularization, collagen remodeling, and inflammatory markers in a diabetic mouse model. Results: PEG-HS/TiO2 achieved sustained HS release over 72 hours. It scavenged superoxide and H2O2, reduced endothelial ROS by approximately 89%, suppressed senescence markers, and restored VEGF expression (> 7-fold increase vs. H2O2 control). The nanocomposite shifted macrophages from M1 to M2 phenotype, increasing the CD206/CD86 ratio. In vivo, PEG-HS/TiO2 accelerated wound closure (76% wound area reduction by day 7 vs. 18% in Sham), enhanced CD31+ vessels (6.3-fold vs. Sham), improved collagen organization, reduced M1 macrophages by 85% and IL-1β by 73%, increased IL-10 by 3.1-fold, and lowered systemic CRP and PCT. Discussion: PEG-HS/TiO2 breaks the diabetic wound pathology cycle through ROS neutralization, anti-senescence, and macrophage immunometabolic reprogramming, representing a promising strategy for diabetic wound management. Keywords: diabetic wound healing, nanozyme, reactive oxygen species, macrophage polarization, immunometabolic reprogramming, honeysuckle