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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\u2010responsive delivery system for microRNA\u201021 (miR\u201021) and DB1976 (a PU.1 inhibitor) to remodel the cardiac environment in a relatively comprehensive way. MiR\u201021 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\u201021. In a mouse MI model, the hydrogel (termed mesoporous silica nanoparticles (MSN)\/miR\u201021\u2010DB 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.<\/jats:p>","DOI":"10.1002\/adhm.202505502","type":"journal-article","created":{"date-parts":[[2026,1,25]],"date-time":"2026-01-25T06:45:10Z","timestamp":1769323510000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["One Stone, Four Birds: Multiple Modulation of Infarct Microenvironment\u2010Based ROS\u2010Responsive Hydrogel for Cardiac Repair"],"prefix":"10.1002","volume":"15","author":[{"given":"Kai","family":"Feng","sequence":"first","affiliation":[{"name":"State Key Laboratory of Natural Medicines Key Laboratory of Drug Quality Control and Pharmacovigilance School of Pharmacy China Pharmaceutical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiajia","family":"An","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Natural Medicines Key Laboratory of Drug Quality Control and Pharmacovigilance School of Pharmacy China Pharmaceutical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinmiao","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Natural Medicines Key Laboratory of Drug Quality Control and Pharmacovigilance School of Pharmacy China Pharmaceutical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaoling","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Natural Medicines Key Laboratory of Drug Quality Control and Pharmacovigilance School of Pharmacy China Pharmaceutical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiling","family":"Ruan","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Natural Medicines Key Laboratory of Drug Quality Control and Pharmacovigilance School of Pharmacy China Pharmaceutical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongxiang","family":"Huang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Natural Medicines Key Laboratory of Drug Quality Control and Pharmacovigilance School of Pharmacy China Pharmaceutical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanlei","family":"Sun","sequence":"additional","affiliation":[{"name":"General Practice Department Nanjing Hospital of Chinese Medicine affiliated to Nanjing University of Chinese Medicine  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuan","family":"Liu","sequence":"additional","affiliation":[{"name":"Research Center The Second Hospital of Nanjing Affiliated to Nanjing University of Chinese Medicine  Nanjing P. 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