Checkpoint nano-degrader to transiently promote efferocytosis in acute myocardial infarction

Abstract The efferocytosis of apoptotic cardiomyocytes (CMs) after acute myocardial infarction (AMI) is required for inflammation resolution and cardiac repair. However, this process would be impaired by the elevated CD47 presentation on apoptotic CMs. Herein, we developed CD47 density-controlled senescent RBC-mimetic liposome (RLP) as a nano-degrader to promote receptor signal-regulatory protein alpha (SIRPα) mediated internalization and transiently inhibit CD47-SIRPα axis. We demonstrated that RLP modified with Ly6G antibody hitchhiked neutrophiles and was released to macrophages in the border area of the infarct heart, which was subsequently internalized through SIRPα and degraded in lysosome. CD47-SIRPα axis blockade consequently promoted the efferocytosis of apoptotic CMs and lead to decreased infarct area and anti-inflammatory microenvironment for improved cardiac remodeling. This nano-degrader from senescent RBC-mimetic liposome presents a practical membrane protein degradation strategy to transiently inhibit CD47-SIRPα axis and boost apoptotic CMs efferocytosis.