Biomimetic Nano-Degrader Based CD47-SIRP Immune Checkpoint Inhibition Promotes Macrophage Efferocytosis for Cardiac Repair

CD47-SIRP alpha axis is an immunotherapeutic target in tumor therapy. However, current monoclonal antibody targeting CD47-SIRP alpha axis is associated with on-target off-tumor and antigen sink effects, which significantly limit its potential clinical application. Herein, a biomimetic nano-degrader is developed to inhibit CD47-SIRP alpha axis in a site-specific manner through SIRP alpha degradation, and its efficacy in acute myocardial infarction (AMI) is evaluated. The nano-degrader is constructed by hybridizing liposome with red blood cell (RBC) membrane (RLP), which mimics the CD47 density of senescent RBCs and possesses a natural high-affinity binding capability to SIRP alpha on macrophages without signaling capacity. RLP would bind with SIRP alpha and induce its lysosomal degradation through receptor-mediated endocytosis. To enhance its tissue specificity, Ly6G antibody conjugation (aRLP) is applied, enabling its attachment to neutrophils and accumulation within inflammatory sites. In the myocardial infarction model, aRLP accumulated in the infarcted myocardium blocks CD47-SIRP alpha axis and subsequently promoted the efferocytosis of apoptotic cardiomyocytes by macrophage, improved heart repair. This nano-degrader efficiently degraded SIRP alpha in lysosomes, providing a new strategy for immunotherapy with great clinical transformation potential.