Engineered heterojunction microneedles initiate ROS-mediated “two-hit” mechanism for accelerating impaired wound healing in diabetes

Wound dressings are developed to produce reactive oxygen species (ROS) by consuming glucose, offering ideal antibacterial activity in diabetes. However, declining glucose levels restrict ROS production, impairing antibacterial and pro-regenerative efficacy. This study aims to fabricate a wound dressing with sustained ROS-producing and antibacterial abilities. Firstly, we propose a “two-hit” strategy: ROS production is initially glucose oxidase (GOx)-dominated during early healing, while the Fenton reaction sustains ROS generation post-glucose depletion. We also design a CNOH/MXene heterojunction (C@M). Initially, it consumes glucose to produce ROS via near-infrared (NIR)-activated GOx activity, and then it maintains ROS via the Ti-mediated Fenton reaction. The heterojunction was integrated into gelatin methacryloyl microneedles, forming a dual-layer system (GC@M). Experimental validation confirmed GC@M accelerates diabetic wound healing through this two-hit mechanism. Further studies revealed ROS exerts antibacterial effects by triggering lipid peroxidation-related bacterial membrane damage and cell death. This work presents a transformative two-hit mechanism for diabetic wound management. • A “two-hit” strategy was proposed by combining GOx-like nanozyme and Fenton reaction • C@M heterojunction was incorporated into microneedles for accelerating wound healing • GC@M microneedles eliminated bacterial infection by inducing LPO-related membrane damage Diabetic wound healing is severely impaired by hyperglycemia and bacterial infection. In recent years, bioactive wound dressings have been developed to consume glucose and generate reactive oxygen species (ROS), offering ideal antibacterial and pro-regenerative abilities. However, the generation of antibacterial ROS is glucose-dependent; therefore, a decline in glucose concentration at a later stage of wound healing reduces ROS levels and diminishes antibacterial efficacy. In this study, we propose a “two-hit” strategy: ROS production is initially glucose oxidase (GOx)-dominated during early healing, while the Fenton reaction sustains ROS generation post-glucose depletion. We further design a CNOH/MXene heterojunction (C@M) and composite microneedle system (GC@M): C@M heterojunction is prepared by anchoring MXene (Ti 3 C 2 ) quantum dots onto alkalinized g-C 3 N 4 (CNOH) nanosheets and then integrated into gelatin methacryloyl microneedles. We found that GC@M microneedles produce ROS through this two-hit mechanism and inhibit bacterial proliferation and survival by triggering lipid peroxidation-related bacterial membrane damage and cell death. In conclusion, this work offers a transformative two-hit hypothesis as a clinically viable solution. Diabetic wound healing is severely impaired by hyperglycemia and bacterial infection. For nanozyme-based wound dressings, a decline in glucose concentration at a later stage of wound healing reduces ROS levels and diminishes antibacterial efficacy. Wang et al. propose a “two-hit” strategy and design a C@M heterojunction and composite GC@M microneedle system to solve this problem. Such microneedles inhibit bacterial proliferation and survival by triggering LPO-related bacterial membrane damage and cell death, confirming the transformative two-hit hypothesis as a clinically viable solution.