A Co-Doped Fe3O4 Nanozyme Shows Enhanced Reactive Oxygen and Nitrogen Species Scavenging Activity and Ameliorates the Deleterious Effects of Ischemic Stroke.

ABSTRACT

Acute ischemic stroke has become the major cause of mortality and disability worldwide. Following ischemic stroke, the reperfusion injury is mainly mediated by the burst of reactive oxygen and nitrogen species (RONS). Therefore, blocking the excessive production or removing RONS holds great promise as a potential therapeutic strategy. Herein, we developed a Co-doped Fe3O4 nanozyme that is capable of scavenging H2O2, O2•-, •NO, and ONOO- in vitro and in vivo and provides neuroprotection against ischemic stroke. In vitro experiments showed that pre-incubation with the Co-Fe3O4 nanozyme could prevent neurotoxicity and neuroinflammation induced by H2O2 or lipopolysaccharide, respectively, in HT22 cells. After intravenous administration, the Co-Fe3O4 nanozyme showed no signs of toxicity in peripheral organs of C57BL/6J mice, even after prolonged delivery for 4 weeks. In permanent photothrombotic stroke model and transient middle cerebral artery occlusion stroke model, the Co-Fe3O4 nanozyme specifically accumulated in the infarct rim at 72 h post-stroke and was endocytosed by neurons, astrocytes, microglia, and endothelial cells. Importantly, the Co-Fe3O4 nanozyme delivery reduced the infarct volume in both stroke models. The observation that the Co-Fe3O4 nanozyme was efficacious in two well-characterized ischemic stroke models provides strong evidence that it represents a powerful tool for targeting oxidative and nitrosative stress in the ischemic brain.