Inflammation-targeted single-atom nanozymes drive microglial depolarization and inhibit ferroptosis via Sirt-6-xCT-GPX4 axis to attenuate early brain injury following subarachnoid hemorrhage

Early brain injury (EBI) has been identified as a key factor leading to the poor prognosis of patients with subarachnoid hemorrhage (SAH). At present, apart from surgical treatment, there is a lack of effective neuroprotective drugs. In this study, a biomimetic nanozyme V-MDL-800 was constructed by coordinating Vanadium Single-atom enzymes (V/SAE) and the allosteric activator MDL-800 of Sirt6, and encapsulated into NM@V-MDL-800 with neutropenia cell membrane (NM). By clearing ROS, the xCT/GPX4 pathway was activated, blocking the pathophysiological process of EBI after SAH can improve prognosis. NM@V-MDL-800 recruits through the blood-brain barrier (BBB) at the site of hemorrhagic injury by relying on the chemotactic property of neutrophils. Among them, the catalase-like, superoxide dismutase-like, and hydroxyl radical scavenging effects of V/SAE can eliminate excessive reactive oxygen species (ROS) within cells and inhibit oxidative stress; at the same time, as an allosteric activator of Sirt6, it activates the downstream xCT/GPX4 pathway, improving lipid metabolism abnormalities. Regulating the key core pathway of lipid peroxidation on ferroptosis promotes the polarization of microglia from the pro-inflammatory M1 form to the anti-inflammatory M2 morphology to inhibit the pathophysiological process of neuroinflammation in EBI. In addition, in vivo imaging of mice confirmed the targeted effect of NM@V-MDL-800 through the blood-brain barrier and recruited at the site of bleeding injury. The therapeutic effect of NM@V-MDL-800 on the SAH model has also been confirmed in vivo and in vitro experiments. This provides new ideas for SAH drug therapy regimens of SAH targeting microglial ferroptosis.