Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, 20032, China.
National Clinical Research Center for Interventional Medicine, Shanghai Clinical Research Center for Interventional Medicine, 180 Feng Lin Road, Shanghai, 200032, China.
Adv Sci (Weinh). 2024 Jun;11(24):e2306388. doi: 10.1002/advs.202306388. Epub 2024 Mar 13.
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.
CD47-SIRPα 轴是肿瘤治疗的免疫治疗靶点。然而，目前针对 CD47-SIRPα 轴的单克隆抗体与靶标脱靶和抗原消耗效应有关，这显著限制了其潜在的临床应用。本文构建了一种仿生纳米降解剂，通过 SIRPα 降解以特异性方式抑制 CD47-SIRPα 轴，并评估其在急性心肌梗死（AMI）中的疗效。该纳米降解剂通过将脂质体与红细胞（RBC）膜（RLP）杂交构建而成，模拟衰老 RBC 上的 CD47 密度，并具有与巨噬细胞上 SIRPα 天然高亲和力结合的能力，而没有信号传导能力。RLP 会通过受体介导的内吞作用与 SIRPα 结合，并诱导其溶酶体降解。为了增强其组织特异性，应用了 Ly6G 抗体缀合（aRLP），使其能够附着于中性粒细胞并在炎症部位聚集。在心肌梗死模型中，聚集在梗死心肌中的 aRLP 阻断了 CD47-SIRPα 轴，随后促进了巨噬细胞对凋亡心肌细胞的吞噬作用，改善了心脏修复。这种纳米降解剂能有效地在溶酶体中降解 SIRPα，为具有巨大临床转化潜力的免疫治疗提供了一种新策略。
