ROS-responsive multifunctional hyaluronic acid/gelatin based adhesive hydrogel encapsulating baicalin and cerium dioxide nanozymes accelerates infected diabetic wounds healing

The management of chronic wounds in diabetic patients continues to pose a substantial clinical challenge, especially when complicated by methicillin-resistant Staphylococcus aureus (MRSA) infection, which exacerbates inflammation and impedes the healing process. To address this, we developed a Reactive Oxygen Species(ROS)-responsive, self-healing multifunctional hydrogel (HA/Gel@CeO₂@BA) incorporating baicalin (BA) and cerium dioxide (CeO₂) nanozymes with superoxide dismutase and catalase activities to synergistically provide antibacterial, antioxidant, anti-inflammatory, and pro-regenerative effects. The hydrogel comprises a dual-network structure: (1) a dynamic Schiff base-crosslinked network formed between hydrazine-modified hyaluronic acid (HA-DTPH) (containing disulfide bonds) and aldehyde-modified HA (HA-CHO), enabling tissue adhesion through amino-aldehyde bonding; and (2) a secondary network of gelatin methacrylate (GelMA) and acryloylated cyclodextrin, which anchors hydrophobic BA for sustained release. Dynamic Schiff base bonds and disulfide bonds undergo diabetes-responsive degradation via pathways involving reactive oxygen species, enabling drug release in response to the local environment. In vitro, HA/Gel@CeO₂@BA was found to scavenge ROS in macrophages, promote M2 polarization and enhance angiogenesis. It also exhibited strong antibacterial effects against Escherichia coli and S. aureus. In a diabetic rat model of infected wounds, the hydrogel significantly reduced the bacterial load and accelerated the healing process without the need for external intervention. This strategy combines ROS-triggered drug release and multifunctional therapeutic effects with biodegradability, demonstrating its high potential for clinical translation in the treatment of infected chronic wounds.