Ultrasound-responsive hydrogel with ROS scavenging and NO controllable release capabilities for accelerated healing of diabetic wounds

Diabetic wounds represent a common and challenging complication of diabetes mellitus, characterized by a complex pathological microenvironment that includes excessive reactive oxygen species (ROS), chronic inflammation, hypoxia, and impaired nitric oxide (NO) synthesis. These factors collectively contribute to delayed wound healing, increased infection risk, and potential progression to chronic non-healing ulcers. Herein, we constructed a multifunctional injectable hydrogel (Prussian blue nanozyme and S-nitrosothiol-loaded hydrogel, PBE&SNO@HG) co-loaded with multi-enzyme-mimicking Prussian blue nanozymes (PBE) and an ultrasound-responsive nitric oxide (NO) donor (SNO). This composite hydrogel exhibited favorable injectability and tissue adhesiveness. The incorporated PBE nanozymes simultaneously mimicked superoxide dismutase (SOD) and catalase (CAT), enabling the scavenging of superoxide anions (⋅O 2 - ) and hydrogen peroxide (H 2 O 2 ), thereby reducing oxidative stress levels at the wound site. Additionally, the ultrasound (US)-responsive release of NO promoted angiogenesis and alleviates inflammatory responses in the wound area. Animal experiments demonstrated that this hydrogel system significantly enhances collagen deposition, accelerates re-epithelialization, promotes hair follicle regeneration, and accelerates wound healing. This study demonstrated the synergistic effect of combining antioxidant strategies with gas therapy in diabetic wound treatment, while also indicating that US-responsive hydrogel materials can achieve on-demand release of therapeutic molecules via external field stimulation, thereby providing a novel strategy for chronic wound management. PBE&SNO@HG is an injectable hydrogel containing Prussian blue nanozymes (PBE) and an ultrasound-responsive nitric oxide (NO) donor (SNO). By integrating a Prussian blue nanozyme (PBE) for ROS scavenging and an ultrasound-responsive nitric oxide donor (SNO) for controlled NO release, the system synergistically accelerates diabetic wound healing through the coordinated regulation of inflammation, oxidative stress, and cell migration. The synergistic strategy of ultrasound-triggered NO release and concurrent ROS scavenging collectively remodels the wound microenvironment. The ultrasound-responsive PBE&SNO@HG system significantly down-regulated inflammatory factors (e.g., TNF-α and IL-6) while up-regulating key pro-angiogenic (e.g., CD31 and VEGF) and pro-migratory markers (e.g., TGF-β). These regulated factors collectively demonstrate a synergistic therapeutic effect on diabetic wounds, underpinning the system's capacity for multi-mechanistic healing. • Ultrasound (US)-triggered on-demand NO release via S–N bond cleavage in SNO enables precise spatiotemporal control at diabetic wounds. • Injectable PBE&SNO@HG exhibits component stability and favorable wound coverage capability. • Synergistic “NO release–ROS scavenge” cascade from PBE (SOD-/CAT-like nanozyme) and US-responsive SNO accelerates diabetic wound closure via anti-inflammation, pro-angiogenesis, and pro-proliferation.