“Electron transport chain interference” strategy of amplified bacterial ferroptosis and defect-engineered nanozyme for diabetic wound healing

<b>Background:</b> The pathological hyperglycemic microenvironment in diabetic wounds increases susceptibility to bacterial infections and impairs wound healing. However, despite certain advancements in conventional clinical treatments, the pathological issues have not yet been fundamentally resolved. The mechanism that amplifies ferroptosis through disruption of the bacterial electron transport chain (ETC) results in effective bacterial eradication and facilitates wound healing, thereby offering novel therapeutic potential for the management of diabetic wound infections. <b>Methods:</b> This work designs a multi-enzyme-mimicking Fe-WS₂@GOx nanozymes by loading glucose oxidase (GOx) onto defect-engineered Fe-WS₂, which disrupts the bacterial ETC and induces ferroptosis, thereby accelerating diabetic wound healing. <b>Results:</b> During the bacterial infection stage, the Fe-WS₂@GOx nanozymes with abundant sulfur vacancies can simultaneously mitigate hyperglycemic and alleviate the hypoxic microenvironment. This is achieved through continuously producing substantial amounts of reactive oxygen species (ROS), resulting in endogenous glucose consumption, promoting cyclic accumulation of H₂O₂, and ensuring a sustained oxygen supply. Meanwhile, the generated ROS interferes with the bacterial ETC, impedes bacterial energy metabolism and inhibits biosynthesis, ultimately leading to bacterial death. More importantly, at the new tissue proliferation stage, Fe-WS₂@GOx can promote wound angiogenesis and tissue regeneration by macrophage immunomodulatory effect. <b>Conclusions:</b> Therefore, this study provides a new paradigm strategy for diabetic wound infections therapy by "electron transport chain interference" amplified bacterial ferroptosis.