Potent antioxidative drugs are urgently needed to treat ischemia-reperfusion (I/R) induced reactive oxygen species (ROS)-mediated cerebrovascular and neural injury during ischemia strokes. However, current antioxidative agents have limited application in such disease due to low blood-brain barrier (BBB) penetration. We herein designed a "neutrophil piggybacking" strategy based on albumin opsonized nanoparticles co-encapsulated with antioxidases catalase (CAT) and superoxide dismutase 1 (SOD1). The system utilized the natural potential of neutrophils to target inflamed tissues to deliver antioxidases to injured sites in the brain. In addition, the system was integrated with a selenium (Se)-containing crosslinker to inhibit ferroptosis. We showed that the nanoparticles opsonized in the hybrid form rather than with an albumin-shell structure exhibited enhanced neutrophil targeting and efficient BBB penetration in vitro and in vivo. We further showed that the neutrophil-mediated delivery of antioxidases effectively reduced oxidative damage and apoptosis of neurons in brain tissue in a transient middle cerebral artery occlusion (tMCAO) mouse model. Moreover, the successful delivery of Se with the nanoparticles increased the expression of glutathione peroxidase 4 (GPX4) and effectively inhibited neuronal ferroptosis, achieving a satisfactory neuroprotective effect in I/R injury mice. Our study demonstrated that the rationally designed nanomedicines using the "neutrophil piggybacking" strategy can efficiently penetrate the BBB, greatly expanding the application of nanomedicines in the treatment of central nervous system (CNS) diseases.