Artificial multienzyme nanoflower composite hydrogel for efficiently promoting MRSA-infected diabetic wound healing via glucose-activated NO releasing and microenvironment regulation

Diabetic wound repair is a global challenge due to bacterial infection and the typical microenvironments of hyperglycemia, high pH value, hypoxia, persistent inflammation and insufficient angiogenesis. Herein, a glucose-activated nitric oxide (NO) releasing and microenvironment regulation hydrogel dressing (COH-GB) has been developed for efficiently promoting infectious diabetic wound healing. Specifically, an artificial multienzyme nanoflower (GB nanoflower) composed of glucose oxidase (GOx) and hemoglobin (Hb) was synthesized and incorporated into the hydrogel formed by carboxymethyl chitosan (CMCS), oxidized sodium alginate (OSA) and hydroxyurea (HU). In which, the hyperglycemia-triggered cascade reaction could consume glucose, while providing hydrogen peroxide (H₂O₂) for the generation of NO by HU in the presence of Hb with peroxidase-mimicking activity. The COH-GB hydrogel with essential wound dressing characteristics could remodel the microenvironment of diabetic wounds by reducing local glucose and pH levels, alleviating hypoxia, and scavenging excessive ROS; and releasing NO under different blood glucose levels for antibacterial or angiogenesis. Importantly, the prepared COH-GB hydrogel significantly accelerated the MRSA-infected diabetic wound healing by effectively reducing wound infection, inhibiting inflammation, and promoting collagen deposition, angiogenesis and the migration and differentiation of fibroblasts and keratinocytes. Notably, the formation of GB nanoflowers could enhance the activity and stability of enzymes, and improve the cascade reaction efficiency, thereby inducing a more efficient performance in microenvironment regulation, antibacterial and angiogenesis, as well as wound healing. Hence, the prepared artificial multienzyme nanoflower composite hydrogel provides an efficient and secure dressing for promoting infectious diabetic wound healing via glucose-activated NO releasing and microenvironment regulation.