Ultrasound-Augmented Multienzyme-like Nanozyme Hydrogel Spray for Promoting Diabetic Wound Healing

Treatment of diabetic foot ulcers (DFU) needs to reduceinflammation,relieve hypoxia, lower blood glucose, promote angiogenesis, and eliminatepathogenic bacteria, but the therapeutic efficacy is greatly limitedby the diversity and synergy of drug functions as well as the DFUmicroenvironment itself. Herein, an ultrasound-augmented multienzyme-likenanozyme hydrogel spray was developed using hyaluronic acid encapsulated l-arginine and ultrasmall gold nanoparticles and Cu1.6O nanoparticles coloaded phosphorus doped graphitic carbon nitridenanosheets (ACPCAH). This nanozyme hydrogel spray possesses five typesof enzyme-like activities, including superoxide dismutase (SOD)-,catalase (CAT)-, glucose oxidase (GOx)-, peroxidase (POD)-, and nitricoxide synthase (NOS)-like activities. The kinetics and reaction mechanismof the sonodynamic/sonothermal synergistic enhancement of the SOD-CAT-GOx-POD/NOScascade reaction of ACPCAH are fully investigated. Both in vitro andin vivo tests demonstrate that this nanozyme hydrogel spray can beactivated by the DFU microenvironment to reduce inflammation, relievehypoxia, lower blood glucose, promote angiogenesis, and eliminatepathogenic bacteria, thus accelerating diabetic wound healing effectively.This study highlights a competitive approach based on multienzyme-likenanozymes for the development of all-in-one DFU therapies.