A bio-inspired synthetic efferocytosis chimeric receptor restores macrophage efferocytosis and inflammatory resolution after cardiac injury

Inflammation that fails to resolve after cardiac injury is a major driver of adverse tissue remodeling and heart failure. A central contributor to this failure is defective efferocytosis, in which macrophages incompletely clear apoptotic cells owing to disrupted coupling between apoptotic recognition and Mertk-dependent resolution signaling under inflammatory stress. Here we develop a bio-inspired efferocytic chimeric receptor (ECR) that restores efferocytosis by directly integrating phosphatidylserine recognition with intact Mertk intracellular signaling. By reconstructing this native clearance pathway at the receptor level, ECR enable macrophages to execute physiological efferocytosis when endogenous signaling is compromised. Using Ly6C antibody-modified lipid nanoparticles (LNP) to deliver ECR mRNA in vivo, we transiently program circulating monocytes and their derivative macrophages in the injured myocardium. In a mice model of cardiac ischemia-reperfusion (MI/R) injury, ECR expression enhanced macrophage efferocytosis, promoted resolution-associated signaling, and attenuates post-infarction inflammation, resulting in reduced tissue injury and improved cardiac function. Macrophages in ECR-treated hearts exhibit transcriptional features consistent with reparative and efferocytosis-linked states. A corresponding human ECR analog similarly enhanced efferocytosis and anti-inflammatory responses in human macrophages in vitro, supporting translational relevance. Together, these findings establish efferocytic receptor engineering combined with in situ mRNA delivery as a strategy to restore defective efferocytosis and enable resolution-focused immunomodulation after cardiac injury.