Hydrogel-Powered Adversity Transformation: On-Demand Ultrasonic Switching Strategy for Accelerating Diabetic Wound Healing

Chronic nonhealing diabetic wounds are characterized by excessive reactive oxygen species (ROS) accumulation, local hypoxia, and bacterial infection, which exacerbate tissue necrosis. Current treatments face challenges in simultaneously effective antibacterial activity, elimination of chronic inflammation, and wound healing against the adverse wound microenvironment. Here, we introduce an injectable polyoxometalate-hyaluronic acid hydrogel (POMHH), which incorporates chemically reduced molybdenum (Mo)-based polyoxometalate (POM) nanoclusters into a dynamically cross-linked hyaluronic acid network. This POMHH demonstrates injectable adhesion and adaptation to irregular wounds while serving as a physical barrier. The POM in POMHH continuously consumes endogenous low toxic hydrogen peroxide (H2O2) to generate strong toxic singlet oxygen (1O2) via an oxygen-independent mechanism, ensuring potent antibacterial activity. By application of ultrasound (US), the hydrogel substrates transmit sound waves to the POM, facilitating rapid Mo ion valence state transformation (Mo5+ to Mo6+), thereby inducing robust elimination of superoxide anions (·O2-), hydroxyl radicals (·OH), and H2O2 for sustained release of oxygen. This spatiotemporal US regulation on POMHH enables alleviating inflammation, regulating macrophage polarization, and promoting epithelial regeneration. In diabetic mouse models with a bacterial-infected wound, the POMHH demonstrates good biocompatibility, antibacterial activity, and US-triggered acceleration of wound healing, showing potential for further clinical applications.