pH and Glutathione-Responsive Sequentially Releasing Hydroxyl Radical and Hydrogen Sulfide Nanozyme for Effective Wound Infection Treatment via Bimodal Chemodynamic-Gas Therapy

Nowadays, bacterial infection-associated diseases pose significant threats to human public health. Developing alternative strategies for the highly efficient treatment of bacterial infections is in urgent demand. It is well-known that hydroxyl radical (^•OH) exhibits strong antibacterial activity and is widely used for chemodynamic therapy (CDT), while hydrogen sulfide (H₂S) displays the ability to promote wound healing for gas therapy (GT). In the present work, a multifunctional nanozyme with pH and GSH dual-responsive sequentially releasing ^•OH and H₂S properties was rationally designed for high-efficiency wound infection treatment via bimodal CDT and GT therapy. Herein, dendritic mesoporous organic silica (DMOS) nanoparticles were prepared and used as the carrier for in situ copper peroxide (CP) nanodots growth, obtaining nanozyme of DMOS@CP. In the acidic condition, CP decorated on DMOS was first decomposed by generating ^•OH via the Fenton-like reaction, which was able to effectively inhibit bacterial growth, as well as eradicate bacterial biofilms, by disrupting the bacterial cell membrane, increasing intracellular ROS generation, and damaging bacterial DNA. Subsequently, DMOS can be further dissociated by GSH to release a substantial amount of H₂S to promote bacterial wound healing. The mechanism study revealed that H₂S was capable of first reversing the inflammatory microenvironment of the wound by reprogramming M2-type macrophage polarization, followed by upregulating expressions of hypoxia-inducible factor-1α, vascular endothelial growth factor, and CD31 to promote cell migration and angiogenesis.