Microglial Membranes Wrapped Ultrasmall Medium‐Entropy Ru Single‐Atom Nanozyme: Enhanced Catalysis for Accelerating Inflammation/Redox Microenvironment Regulation in Intracerebral Hemorrhage

ABSTRACT Intracerebral hemorrhage (ICH) causes severe secondary brain injury (SBI) via excessive inflammation and reactive oxygen species (ROS), and current treatments lack effective dual‐target efficacy. In this study, we designed a microglial membrane‐wrapped single‐atom nanozyme (PtRhIr/Ru SAN@M) by anchoring a single atom of Ru onto ultrasmall, medium‐entropy PtRhIr alloys. This design integrates two underutilized strategies, single‐atom nanozymes (SANs) and medium‐entropy catalysts, to address critical therapeutic gaps in ICH therapy. PtRhIr/Ru SAN@M exhibited enhanced catalytic activity with superior Hydroxyl radical (•OH) scavenging and superoxide dismutase (SOD)‐like and catalase (CAT)‐like performances compared to Ru‐free PtRhIr@M, enabled by electronically modulated active sites. Fluorescence imaging confirmed its ability to penetrate the blood‐brain barrier (BBB) and accumulate in post‐ICH neuroinflammatory regions. Both in vitro and in vivo experiments demonstrated that PtRhIr/Ru SAN@M repolarized microglia from the M 1 to the M 2 phenotype, disrupting the neuroinflammatory cycle and halting neuronal death. Therapeutic intervention with PtRhIr/Ru SAN@M significantly increased survival rates, restored neurological function, and enhanced spatial memory after ICH. This study pioneers the integration of SANs with medium‐entropy alloys for ICH, offering a dual‐target ROS‐inflammation regulatory strategy and a generalizable platform for ROS‐related degenerative disease therapies.