Hyperglycemia-responsive nitric oxide-releasing biohybrid cryogels with cascade enzyme catalysis for enhanced healing of infected diabetic wounds

Diabetic wound infections are a frequent complication for diabetic patients, and conventional treatment for combating diabetic wound infections relies on antibiotics. However, the misuse and overuse of antibiotics have led to the emergence of drug-resistant bacteria, making these infections challenging to treat. Thus, there is an urgent need for alternative strategies to effectively manage diabetic wound infections. Herein, we have developed a hyperglycemia-responsive antibacterial cryogel system that can generate and release hydrogen peroxide (H 2 O 2 ) and nitric oxide (NO). This system involves incorporating glucose oxidase (GO) and L-Arginine (L-Arg: A) into hyaluronic acid aldehyde methacryloyl (HAAMA: H) and gelatin methacryloyl (GelMA: G) hybrid cryogels (GOA@HG). HAAMA facilitated higher loading and longer stability of L-Arg and GO via a Schiff base reaction. In vitro studies demonstrate that GOA@HG cryogels exhibited outstanding breathability, effective exudate management, and excellent hemostasis capabilities. Moreover, this system could consume excess glucose in diabetic wounds and efficiently eliminate bacteria through the cascaded release of H 2 O 2 and NO without causing antibiotic resistance. In vivo studies further reveal that GOA@HG cryogels significantly enhanced the healing of infected diabetic wounds by inhibiting bacterial growth, accelerating blood vessel formation, and promoting collagen deposition. Overall, GOA@HG cryogels displayed remarkable wound dressing properties and synergistic antimicrobial effects owing to glucose-responsive H 2 O 2 and NO release, which could serve as a highly efficient therapeutic strategy for treating infected diabetic wounds.