Multifunctional nanogel dressings with dual acid and H2O2 responsive release for synergetic therapy of diabetic bacterial wounds

The high sugar and alkaline environment at diabetic skin wounds promotes the breeding and reproduction of bacteria, leading to insufficient angiogenesis, which seriously affects wound healing. To accelerate wound healing, MnO₂ nanoparticles (MnO₂ NPs) and glucose oxidase (GOD) were added into the acidic and hydrogen peroxide (H₂O₂)-responsive antimicrobial dynamic covalent nano-networks (aDCNs) to form a new aDCNs/MnO₂@GOD nanogel dressing with multiple functions, such as hypoglycemic, anti-bacterial, anti-biofilm, anti-inflammatory, and promoting angiogenesis. The nanogel formation mechanism, physicochemical characterization, responsiveness release, <i>in vitro</i> and <i>in vivo</i> antimicrobial activities, <i>in vivo</i> regeneration in a bacterial-infected mouse model, and anti-inflammatory mechanism were systematically studied. The successfully prepared dressing exhibited obvious acidic and H₂O₂-responsive release, which allows for the quick release of quercetin, MnO₂ NPs, and GOD. The dressing showed on-demand antibacterial and antibiofilm activity by destroying the bacterial cell membranes and cell walls. According to the results of wound healing and anti-inflammation, the nanogel dressing had satisfactory therapeutic effects and effectively regulated the oxidative stress microenvironment, inducing macrophage polarization from pro-inflammatory M1 to anti-inflammatory M2 phenotype. The demonstrated therapeutic effects of the prepared dressing included the full thickness of the diabetic wounds, as shown in a bacterial-infected mouse model. It is anticipated that the nanogel dressing could be employed as an excellent biocompatible wound healing material, which can synergistically overcome the therapeutic difficulty of diabetic bacterial wounds.