A metabolic reprogramming and trained immunity hydrogel mimic cluster missiles to eliminate infection and treat infected diabetic wounds

Excessive inflammation, infection, persistent reactive oxygen species (ROS) accumulation, hyperglycemia, and vascular lesions in diabetic chronic wounds severely impair healing. Currently, there is no treatment regimen available to improve the complex microenvironment of such wounds. We have designed a comprehensive microenvironment intervention system, namely the composite dressing CVCeCG. The injectability, self-healing properties, and tissue adhesion of hydrogel make it an ideal physical barrier. The CVCeCG hydrogel incorporates a photothermal therapy (PTT) strategy, enabling photothermal activation of a missile-like bactericidal program to eliminate infections rapidly. Additionally, CVCeCG hydrogel remodels the immune microenvironment, constructs a dynamic regulatory network of epidermal/dermal cells, macrophages, and blood vessels through immune training and metabolic reprogramming. Even after the dressing is removed, it can still promote wound healing and has long-term effects. Furthermore, this hydrogel dressing alleviates wound hypoxia and reduces ROS levels, thereby further mitigating inflammation and promoting tissue repair. In the diabetic rat model with MRSA-infected wounds, the CVCeCG hydrogel significantly eliminated infection, reduced local inflammatory responses and ROS levels, and established a mutually supportive cycle between improved immune microenvironment and angiogenesis, thereby promoting wound healing. In summary, this work provides significant insights into the use of photothermal therapy to eliminate bacteria and improve the immune microenvironment through immune training and metabolic reprogramming, offering new strategies for comprehensively improving the microenvironment of chronic wounds in diabetes. A hydrogel (CMC-PDA/GEL) was created by combining gelatin (GEL) with catechol-modified carboxymethyl cellulose (CMC-DA). Composite hydrogel dressings in CVCeCG were created by adding polycaprolactone microspheres loaded with calcium peroxide (CPO@PCL) or vancomycin (Van@PCL) and cerium oxide nanoparticles (CeNPs) to CMC-PDA/GEL. This hydrogel can mimic missiles to eliminate infections quickly, remodel the local immune microenvironment by training the immune system and metabolic reprogramming, and clear ROS, establishing a comprehensive microenvironment intervention system, which helps wounds heal.