A Single H₂S-Releasing Nanozyme for Comprehensive Diabetic Wound Healing through Multistep Intervention

Diabetic wound healing presents a significant medical challenge and requires multistep interventions due to comprehensive wound environments, such as hyperglycemia, bacterial infection, and impaired angiogenesis. However, current multistep interventions are complicated and need on-demand sequential release and synergy of multicomponents. Herein, a H₂S-releasing cascade nanozyme (FeS@Au), which is composed of ultrasmall gold nanocluster (AuNC) loaded on ferrous sulfide nanoparticle (FeSNP), is developed as a single component to regulate glucose level, eliminate infection, and promote angiogenesis, achieving multistep interventions for comprehensive diabetic wound treatment. The glucose oxidase-like activity of AuNC catalyzes glucose into gluconic acid and H₂O₂, which not only lowers the local glucose level but also decreases the local pH and increases H₂O₂ level to boost the peroxidase-like activity of FeSNP to generate abundant hydroxyl radical (reactive oxygen species, ROS), inducing ferroptosis-like death in drug-resistant bacteria. Additionally, FeSNP release H₂S in the acidified environment to upregulate hypoxia-inducible factor-1 to enhance vascularization through upregulating the expression of vascular endothelial growth factor (VEGF) and other angiogenesis-related genes, reducing the damage to endothelial cells caused by excessive ROS produced by the nanozyme. In a full-thickness MRSA-infected diabetic rat model, FeS@Au significantly eliminates bacteria, enhances angiogenesis, promotes collagen deposition, and accelerates wound healing. This work presents a single nanozyme with H₂S-release for multistep interventions, providing a versatile strategy for healing extensive tissue damage caused by diabetes.