Multifunctional Silver‐Enzyme Nanogels Assembly with Efficient Trienzyme Cascades for Synergistic Diabetic Wound Healing

Abstract Diabetic wound healing presents a persistent clinical challenge, often characterized by prolonged healing times, and can be particularly difficult to achieve in a hyperglycemic environment. In this study, a multi‐functional silver‐enzyme nanogels assembly (Ag‐nGHC) is designed by focusing on the complex diabetic wound environment. Glucose oxidase (GOX), horseradish peroxidase (HRP), and catalase (CAT) are modified within polymeric nanogel layers and assembled into a large enzyme cluster with silver ions. The close attachment of three enzymes ensures fast and continuous consumption of a high level of glucose, generation of oxygen, and hydroxyl radicals (•OH) around the wound site. Meanwhile, the silver ions within the Ag‐nGHC assembly act as an effective agent to kill bacteria. This cascade enzyme system significantly improves the microenvironment of the wound site by reducing bacterium infection and alleviating hypoxia as well as hyperglycemia. Sequentially, the improved environment facilitates the later processes including anti‐inflammatory, re‐epithelialization, and angiogenesis, evidenced by enhancing polarization toward M2 macrophages and increasing CD31 signals in this study. Overall, the Ag‐nGHC materials are proven to achieve multifunctional properties toward complicated diabetic wound healing processes (attributes such as adaptability, hypoxia‐alleviated, anti‐hyperglycemic, antimicrobial, anti‐inflammatory, and angiogenic) and showed great potential for the treatment of chronic diabetic wound.