Clusterzyme‐Enabled Oxidative Stress Alleviation and Microglial Polarization Modulation for Efficient Ischemic Stroke Treatment

Intravenously injected Au₇Ag₁ NCs with multi-antioxidant enzyme activities efficiently scavenge reactive oxygen species (ROS), protect neurons, and promote microglial polarization from the M1 pro-inflammatory to M2 anti-inflammatory phenotype, offering a promising nanotherapeutic strategy for ischemic stroke (IS) reperfusion injury.

Abstract

Ischemic stroke (IS) presents a significant challenge to global health, as conventional reperfusion strategies aimed at restoring cerebral circulation paradoxically exacerbate neurological damage. This injury primarily results from the excessive production of reactive oxygen species (ROS) and the initiation of a widespread neuroinflammatory response. In this study, mercaptosuccinic acid (MSA)-coated bimetallic clusterzymes, containing an optimized ratio of Au₇Ag₁ nanoclusters (NCs), are developed for the targeted treatment of IS reperfusion injury. The ultrafine particle size of bimetallic nanoclusters facilitates the penetration across the blood-brain barrier (BBB) and enhances catalytic capacity and enzymatic activity through synergistic effects. Comprehensive in vitro and in vivo studies demonstrate that Au₇Ag₁ NCs provide neuroprotection by efficiently scavenging ROS and modulating microglial polarization, alleviating oxidative stress-induced injury. Furthermore, Au₇Ag₁ NCs play a crucial role in reducing brain tissue damage following reperfusion and promoting long-term neurological function recovery. Notably, RNA sequencing reveals that Au₇Ag₁ NCs impact key molecular pathways linked to apoptosis and inflammation. In summary, this study demonstrates the potential of Au₇Ag₁ NCs as a novel therapeutic approach for IS reperfusion injury and highlights a promising pathway for nanomedicine-based interventions targeting ischemic cerebral disorders.