Reprogramming the Diabetic Wound Microenvironment by Enzyme Cascade-Driven, ROS-Responsive Microspheres

Diabetes represents a major global health burden, and diabetic wounds remain particularly challenging due to delayed healing and high infection risk. A dysregulated wound microenvironment, characterized by hyperglycemia, excessive reactive oxygen species (ROS), and persistent hypoxia, critically impairs angiogenesis and tissue regeneration. Herein, we report a multifunctional microsphere system integrating ROS-responsive curcumin-loaded nanoparticles, glucose oxidase (GOx), and catalase (CAT) to simultaneously regulate glucose, oxygen, and oxidative stress in diabetic wounds. The microsphere system reduces glucose levels through a GOx-mediated oxidation process, generating hydrogen peroxide (H₂O₂), which is subsequently decomposed by CAT into oxygen, thereby alleviating local hypoxia. Notably, excessive ROS-particularly H₂O₂-are not only scavenged but also repurposed as an endogenous oxygen source, enabling sustained oxygen supplementation at the wound site. Meanwhile, ROS-responsive curcumin-loaded nanoparticles enable on-demand drug release in oxidative environments, providing localized antioxidant and anti-inflammatory effects while avoiding premature drug exposure. As a result, the system exhibits efficient glucose reduction, oxygen generation, and ROS scavenging, leading to enhanced angiogenesis, fibroblast migration, and accelerated wound healing. Histological and immunohistochemical analyses further confirm reduced inflammation, increased vascularization, and improved tissue regeneration, with the Cur/Enzyme/Nanoclay@Microsphere formulation demonstrating the most pronounced therapeutic efficacy. Overall, this work presents a promising strategy for diabetic wound management by restoring wound microenvironment homeostasis through coordinated enzymatic cascades and ROS-responsive drug delivery.