Neutrophil membrane-based biomimetic metal-polyphenol self-assembled nanozyme for the targeting treatment of early brain injury following subarachnoid hemorrhage

Abstract

NM@Fe-DMY exhibits catalase (CAT) and superoxide dismutase (SOD)-like activities, effectively converting superoxide anion to harmless oxygen and thereby reducing reactive oxygen species (ROS) levels. Additionally, it activates SLC7A11, facilitating the transport of cysteine/glutathione into cells while suppressing the SPHK1/p-mTOR pathway activity. Ultimately, this promotes increased expression of glutathione peroxidase 4 (GPX4) and inhibits lipid peroxidation (LPO), consequently inhibiting ferroptosis. • NM@Fe-DMY improves the prognosis of early brain injury after subarachnoid hemorrhage. • NM@Fe-DMY reverses ferroptosis and alters microglial polarization. • Neutrophil membranes cross blood–brain barrier and target area of inflammation. Early brain injury (EBI) refers to the immediate injury and neuroinflammation in the brain after subarachnoid hemorrhage (SAH). The current drugs used to treat SAH are inadequate due to their disappointing ability to penetrate the blood–brain barrier (BBB) and their limited anti-inflammatory effects, leading to unsatisfactory therapeutic outcomes for EBI. Herein, we developed a biomimetic nanozyme (Fe-DMY) using a metal-polyphenol self-assembly method, involving the coordination of ferric ion (Fe 3+ ) and dihydromyricetin (DMY), then encapsulated Fe-DMY in neutrophil membranes (NM) to form NM@Fe-DMY, which targets to neuroinflammatory regions. NM@Fe-DMY exhibits strong catalase- and superoxide dismutase-like catalytic activities, suggesting its potential to reduce oxidative stress in SAH. This leads to reduced lipid peroxidation, increased expression of glutathione peroxidase 4 and prevented ferroptosis. Furthermore, The NM@Fe-DMY has demonstrated effective penetration of the BBB in vivo, accumulating in SAH injury region and exhibiting significant therapeutic efficacy including neural function recovery and improvement of spatial memory. Importantly, NM@Fe-DMY also induces the polarization of microglia from M1-like to M2-like subtypes, interrupting the detrimental cycle of neuroinflammation in EBI. This study introduces a new NM-wrapped biomimetic nanozyme strategy for effectively targeting neuroinflammatory regions and enhancing the treatment of EBI following SAH.