Dual‐Defect Engineering of LDH‐Based Nanozymes to Enhance Antioxidative Effects in Ischemia Stroke‐Reperfusion Injury

Abstract Nanozymes, renowned for their antioxidant enzyme‐like activities and superior stability over natural enzymes, hold great promise for treating oxidative stress‐related diseases. However, their therapeutic potential remains constrained by limited catalytic efficiency and suboptimal electron transfer capabilities. To overcome these limitations, a dual‐defect engineering strategy is developed to optimize the design of layered double hydroxide (LDH) nanozymes. Through Zn and Ga dual‐metal doping combined with alkaline etching, E‐MgZnVGa‐LDH nanozymes are constructed featuring synergistic metal and oxygen vacancies. These defects significantly enhance the enzyme‐like activities by optimizing the d‐band center, lowering the Fermi level, and optimizing the charge distribution, thereby improving the scavenging efficiency for reactive oxygen species (ROS) and reactive nitrogen species (RNS). Compared with MgV‐LDH, E‐MgZnVGa‐LDH exhibits superior antioxidant efficacy. In vivo, these nanozymes effectively mitigate oxidative stress‐induced brain damage, reduce astrocyte activation, and suppress downstream inflammation in a stroke reperfusion model. This study highlights the critical role of vacancy defects in regulating nanozyme activity and establishes a framework for the rational design of high‐performance nanozymes for oxidative stress‐related therapies.