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 (HO) 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 HO 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 HO and NO release, which could serve as a highly efficient therapeutic strategy for treating infected diabetic wounds.