One Stone, Four Birds: Multiple Modulation of Infarct Microenvironment‐Based ROS‐Responsive Hydrogel for Cardiac Repair

Myocardial infarction (MI) is a worldwide disease with high prevalence and mortality, but it still lacks efficient therapeutic strategies. Since it has been found that numerous cell types are involved in the pathological changes of MI, including fibroblasts, cardiomyocytes, immune cells, and endothelial cells, targeting a cell type seems no longer the ideal treatment. Here, we developed a ROS-responsive delivery system for microRNA-21 (miR-21) and DB1976 (a PU.1 inhibitor) to remodel the cardiac environment in a relatively comprehensive way. MiR-21 exhibited cardioprotective effects by improving angiogenesis, reducing apoptosis, and combating inflammation. However, the accompanying fibrosis impedes its therapeutic effect. DB1976, as a PU.1 inhibitor, could effectively inhibit fibrosis and alleviate the adverse effects of miR-21. In a mouse MI model, the hydrogel (termed mesoporous silica nanoparticles (MSN)/miR-21-DB hydrogel) significantly improved cardiac function through remodeling cardiomyocytes, macrophages, fibroblasts, and vascular endothelial cells. This work provides a new approach for repairing damaged cardiac tissue by simultaneously regulating multiple cell types in the cardiac microenvironment.