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

Jinfeng Gao; Zhiqing Pang; Qiaozi Wang; Yiwen Tan; Qiyu Li; Haipeng Tan; Jing Chen; Wusiman Yakufu; Zhengmin Wang; Hongbo Yang; Jinyan Zhang; Dili Sun; Xueyi Weng; Qibing Wang; Juying Qian; Yanan Song; Zheyong Huang; Junbo Ge

doi:10.1002/advs.202306388

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

Adv Sci (Weinh). 2024 Mar 13:e2306388. doi: 10.1002/advs.202306388. Online ahead of print.

Authors

Jinfeng Gao^{1

2}, Zhiqing Pang³, Qiaozi Wang^{1

2}, Yiwen Tan^{1

2}, Qiyu Li^{1

2}, Haipeng Tan^{1

2}, Jing Chen^{1

2}, Wusiman Yakufu^{1

2}, Zhengmin Wang^{1

2}, Hongbo Yang^{1

2}, Jinyan Zhang^{1

2}, Dili Sun^{1

2}, Xueyi Weng^{1

2}, Qibing Wang^{1

2}, Juying Qian^{1

2}, Yanan Song^{1

2}, Zheyong Huang^{1

2}, Junbo Ge^{1

2

4}

Affiliations

¹ Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, 20032, China.
² National Clinical Research Center for Interventional Medicine, Shanghai Clinical Research Center for Interventional Medicine, 180 Feng Lin Road, Shanghai, 200032, China.
³ School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery, Ministry of Education, 826 Zhangheng Road, Shanghai, 200030, China.
⁴ Institute of Biomedical Sciences, Fudan University, Shanghai, 20032, China.

PMID: 38477522
DOI: 10.1002/advs.202306388

Abstract

CD47-SIRPα axis is an immunotherapeutic target in tumor therapy. However, current monoclonal antibody targeting CD47-SIRPα 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-SIRPα axis in a site-specific manner through SIRPα 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 SIRPα on macrophages without signaling capacity. RLP would bind with SIRPα 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-SIRPα axis and subsequently promoted the efferocytosis of apoptotic cardiomyocytes by macrophage, improved heart repair. This nano-degrader efficiently degraded SIRPα in lysosomes, providing a new strategy for immunotherapy with great clinical transformation potential.

Keywords: CD47-SIRPÎ± axis; acute myocardial infarction; efferocytosis; receptor-mediated internalization; targeted protein degradation.

Abstract

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