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Cardiac resident macrophages (CRMs) are the primary mediators of cardiac immunity, and they serve a dual role through their shaping of both myocardial injury and post\u2010AMI myocardial repair. To appropriately regulate AMI\u2010associated inflammation, HM4oRL is herein designed, an innovative bifunctional therapeutic nanoplatform capable of inhibiting cardiomyocyte pyroptosis while reprogramming inflammatory signaling. This HM4oRL platform is composed of a core of 4\u2010Octyl itaconate (4\u2010OI)\u2010loaded liposomes, a middle layer consisting of a metal\u2010polyphenol network (MPN) film, and an optimized outer hybrid immune\u2010cell membrane layer. The unique properties of this hybrid membrane layer facilitated HM4oRL targeting to the injured myocardium during early\u2010stage AMI in mice, whereupon the release of 4\u2010Ol and modified MPN synergistically inhibited cardiomyocyte pyroptosis while suppressing inflammatory monocytes\/macrophage responses at the infarcted site. Mechanistically, HM4oRL preserved cardiac metabolic homeostasis through AMPK signaling activation, establishing favorable microenvironmental conditions for the reprogramming of CRM\u2010mediated inflammation. Ultimately, HM4oRL treatment is able to resolve inflammation, enhance neovascularization, and suppress myocardial fibrosis, reducing the infarct size and enhancing post\u2010AMI cardiac repair such that it is an innovative approach to the targeted treatment of AMI.<\/jats:p>","DOI":"10.1002\/advs.202414740","type":"journal-article","created":{"date-parts":[[2025,1,21]],"date-time":"2025-01-21T12:25:57Z","timestamp":1737462357000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Injured Myocardium\u2010Targeted Theranostic Nanoplatform for Multi\u2010Dimensional Immune\u2010Inflammation Regulation in Acute Myocardial Infarction"],"prefix":"10.1002","volume":"12","author":[{"given":"Tao","family":"Zheng","sequence":"first","affiliation":[{"name":"Department of Radiology, Nanjing Jinling Hospital, Affiliated Hospital of Medical School Nanjing University  305 East Zhongshan Road Nanjing 210002 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