<p>Myocardial ischemia/reperfusion (I/R) injury represents a major global health concern, driven by excessive reactive oxygen species (ROS), which closely correlates with subsequent myocardial infarction and fibrosis. Combining ROS scavenging with ischemic myocardium revascularization holds therapeutic promise. However, developing multifunctional therapeutic agents that can simultaneously scavenge ROS and promote angiogenesis remains unreported. Herein, we propose MgSrCeAl-layered double hydroxide (LDH) nanosheets as a multifunctional ROS scavenger and angiogenesis promoter for efficient myocardial I/R injury treatment. MgSrCeAl-LDH nanosheets not only exhibit exceptional hydroxyl radicals (·OH) and superoxide anions (·O₂⁻) scavenging capabilities, which is 1.78 times and 1.61 times that of CeO₂, respectively, but also respond to the ischemia-induced acidic microenvironment to release angiogenic Sr²⁺ with a concentration of 32.65 ppm (pH 5.0), which is conducive to efficient angiogenesis. Specifically, the ROS levels in I/R-injured myocardium decreased to 66.2% of its original value following intervention with MgSrCeAl-LDH nanosheets, while the vascular density in the peri-ischemic myocardium increased by approximately 3.6-fold. Ultimately, the infarcted myocardial area is reduced 60.9% compared to the group without MgSrCeAl-LDH intervention. Mechanistically, MgSrCeAl-LDH nanosheets alleviate myocardial infarction and fibrosis caused by I/R injury through activating PI3K/Akt pathway and inhibiting TGF-β pathway, ultimately improving cardiac function and inhibiting ventricular remodeling.</p> Graphical abstract <p></p>