Neutrophil Hitchhiking Biomimetic Nanozymes Prime Neuroprotective Effects of Ischemic Stroke in a Tailored “Burning the Bridges” Manner

Abstract Reperfusion injury of ischemic stroke, characterized by the uncontrolled production of reactive oxygen species (ROS) and inflammatory reactions, continues to present a major problem in clinical treatment. Neutrophils are forerunners to infiltrate cerebral ischemic regions and contribute to reperfusion injury. Herein, this study reports a tailored “burning the bridges” strategy by designing biomimetic nanozymes (D@HPB@SPM NPs) to diminish reperfusion injury of ischemic stroke. D@HPB@SPM NPs are composed of a sialic acid (SA)‐modified platelet membrane shell and a hollow Prussian blue nanoparticle core loaded with Deoxyribonuclease I (DNase I). Due to the unique binding affinity of SA to L‐selectin, which is abundantly expressed in circulating neutrophils, D@HPB@SPM NPs can effectively hitchhike on neutrophils across the blood‐brain barrier into the injured brain parenchyma after intravenous injection. Following this, neutrophils are activated and unleash D@HPB@SPM NPs through producing neutrophil extracellular traps (NETs). D@HPB@SPM NPs not only relieve oxidative stress injury by efficiently scavenging ROS, but also mitigate neutrophil‐induced reperfusion injury by degrading NETs in a manner similar to “burning the bridges”. The encouraging accumulation of D@HPB@SPM NPs to cerebral ischemic regions and their efficient therapeutic efficacy are systematically validated in ischemic stroke rats. This work offers a fresh insight for ischemic stroke treatment.