Optimizing Vanadium Single‐Atom Nanozyme via Cluster‐Mediated Charge Orchestration for Modulating Immune Homeostasis in Intracerebral Hemorrhage

Abstract

Intracerebral hemorrhage (ICH) triggers excessive reactive oxygen species (ROS) accumulation and persistent neuroinflammation, which synergistically drive progressive neuronal damage and poor neurological functional recovery, severely restricting patient prognosis. Artificial enzymes are hailed for their robustness and economy, yet their catalytic ceiling is often set by an inability to finely sculpt the electronic landscape of active centers. Here, we present VAC‐VSA/NC, a single‐atom nanozyme (SAN) in which vanadium (V) atomic clusters (AC) orchestrate proximal V single atoms (SA), thereby regulating the local charge distribution and igniting a potent ROS for detoxification. Density functional theory calculations revealed that electrons flowing from VAC to VSA active sites drain electron density around the VSA center, reshape the local charge distribution, and promote a rapid ROS detoxification cascade. To realize targeted blood–brain barrier (BBB) penetration for ICH treatment, we fabricated VAC‐VSA/NC@M by coating with M1 microglial membranes. In vivo fluorescence imaging confirms that the VAC‐VSA/NC@M efficiently crosses the BBB and precisely accumulates at hemorrhagic inflammatory lesions. In vitro and in vivo experimental results combined with single‐cell sequencing analysis demonstrate that VAC‐VSA/NC@M effectively converts proinflammatory M1 microglia into an anti‐inflammatory M2 phenotype, terminates the self‐amplifying neuroinflammatory cascade, and inhibits progressive neuronal death.