Double Enzyme Active Hydrogel Program Regulates the Microenvironment of Staphylococcus aureus‐Infected Pressure Ulcers

Abstract The treatment of infected pressure ulcers (IUPs) requires addressing diverse microenvironments. A pressing challenge is to effectively enhance the regenerative microenvironment at different stages of the healing process, tailoring interventions as needed. Here, a dual enzyme mimetic and bacterial responsive self‐activating antimicrobial hydrogel designed to enhance IPUs healing is introduced. This hydrogel incorporates pH‐responsive dual enzyme‐active nanoplatforms (HNTs‐Fe‐Ag) encapsulated within a methacrylate‐modified silk fibroin (SFMA) and dopamine methacrylamide (DMA) matrix. This composite hydrogel exhibits adaptive microenvironment regulation capabilities. Under the low pH microenvironment of bacterial infection, it has excellent antimicrobial activity by self‐activating the •OH generation in conjunction with photothermal effects. Under the neutral and alkaline microenvironment of chronic inflammation, it catalyzes the decomposition of hydrogen peroxide (H 2 O 2 ) to produce oxygen (O 2 ), thereby alleviating hypoxia and scavenging reactive oxygen species (ROS), which in turn remodulates the phenotype of macrophages. The composite hydrogel demonstrates on‐demand therapeutic effects in the microenvironment of infected wounds, significantly enhancing the regenerative microenvironment of IUPs by promoting wound closure, inflammation regulation, and collagen deposition through self‐activated antimicrobial action during infection and adaptive hypoxia relief during recovery. This approach offers a novel strategy for developing smart wound dressings.