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

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 M1 to the M2 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.