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

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.