A Sustained Oxygen- and Nitric Oxide-Producing Hydrogel Accelerates Methicillin-Resistant Staphylococcus aureus-Infected Diabetic Wound Healing under Hypoxia

Chronic inflammation and hypoxia in the diabetic hyperglycemic microenvironment can lead to persistent vascular impairment, hindering tissue regeneration and exacerbating adverse outcomes. We propose a multifunctional regeneration strategy capable of simultaneously releasing oxygen (O₂) and nitric oxide (NO) to enhance immune regulation and angiogenesis, significantly accelerating wound healing. Here, a dual-dynamic-network hydrogel was designed for in situ depletion of excess reactive oxygen species (ROS) and immunomodulation to accelerate the remodeling of MRSA-infected diabetic wounds. The hydrogel was constructed using Schiff base and phenylborate ester bonds, with l-arginine-modified manganese dioxide (ACM) nanoparticles integrated into its framework. This hydrogel could respond to ROS in the diabetic microenvironment and subsequently generate oxygen and nitric oxide. Studies have shown that PDM hydrogel exhibited good biocompatibility, promoted cell migration, and facilitated endothelial cell tubular formation. Mechanistically, in vitro and in vivo analyses revealed that PDM could relieve excessive ROS levels, restore mitochondrial membrane potential, down-regulate pro-inflammatory marker CD86, up-regulate anti-inflammatory marker CD206, and promote macrophage polarization toward a reparative phenotype. In MRSA-infected full-thickness skin wounds, the PDM hydrogel alleviated hypoxia by decomposing endogenous H₂O₂ into O₂ (thereby reducing HIF-1α expression), modulated inflammatory responses (downregulating TNF-α and upregulating CD206), enhanced the expression of angiogenic factors VEGF and CD31, and increased collagen I deposition. These findings suggest that the multifunctional PDM hydrogel holds clinical potential for reshaping the damaged tissue microenvironment and offers an effective therapeutic strategy for chronic skin wound regeneration.