Injured Myocardium‐Targeted Theranostic Nanoplatform for Multi‐Dimensional Immune‐Inflammation Regulation in Acute Myocardial Infarction

Abstract Pyroptosis is a key mode of programmed cell death during the early stages following acute myocardial infarction (AMI), driving immune‐inflammatory responses. 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‐AMI myocardial repair. To appropriately regulate AMI‐associated 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‐Octyl itaconate (4‐OI)‐loaded liposomes, a middle layer consisting of a metal‐polyphenol network (MPN) film, and an optimized outer hybrid immune‐cell membrane layer. The unique properties of this hybrid membrane layer facilitated HM4oRL targeting to the injured myocardium during early‐stage AMI in mice, whereupon the release of 4‐Ol 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‐mediated inflammation. Ultimately, HM4oRL treatment is able to resolve inflammation, enhance neovascularization, and suppress myocardial fibrosis, reducing the infarct size and enhancing post‐AMI cardiac repair such that it is an innovative approach to the targeted treatment of AMI.