Nanozyme‐Reinforced Hydrogel Spray as a Reactive Oxygen Species‐Driven Oxygenator to Accelerate Diabetic Wound Healing

The accumulation of reactive oxygen species (ROS) and poor oxygen supply are two prominent factors of the inflammatory microenvironment that delay diabetic wound healing. However, current clinical treatments cannot achieve effective ROS scavenging and sustained oxygenation. Herein, a ROS-driven oxygenation hydrogel (OxyGel) spray that integrates a multifunctional nanozyme with a dynamically crosslinked sprayable hydrogel matrix is presented. The nanozyme, which is fabricated based on the ceria-zoledronic acid nanoparticles modified with tannic acid (TCZ nanozymes), can mimic the cascade catalytic activities of superoxide dismutase (SOD) and catalase (CAT) to effectively scavenge ROS while generating oxygen. These synergistic actions rebalance the oxidative and hypoxic microenvironment of the diabetic wound, promote M1-to-M2 macrophage repolarization, and enhance the survival, migration, and angiogenesis of endothelial cells. A single administration of the nanozyme via the hydrogel spray stably deposits the nanozymes at the target sites to accelerate full-thickness back skin wound and refractory foot ulcer wound healing in diabetic rats. Furthermore, RNA-seq results revealed the upregulation of multiple signaling pathways related to wound healing by the OxyGel spray, highlighting the potential of this platform not only for the treatment of refractory diabetic wounds but also other diseases associated with oxidative stress and hypoxia.