Dual targeting to immune checkpoints has achieved a better therapeutic efficacy than single targeting due to synergistic extrication of tumour immunity. However, most dual targeting strategies are usually antibody dependent which facing drawbacks of antibodies, such as poor solid tumour penetration and unsatisfied affinity. To meet the challenges, we engineered a cell membrane displaying a fusion protein composed of SIRPα and PD-1 variants, the high-affinity consensus (HAC) of wild-type molecules, and with which prepared nanovesicles (NVs). Through disabling both SIRPα/CD47 and PD-1/PD-L1 signalling, HAC NVs significantly preserved the phagocytosis and antitumour effect of macrophages and T cells, respectively. In vivo study revealed that HAC NVs had better tumour penetration than monoclonal antibodies and higher binding affinity to CD47 and PD-L1 on tumour cells compared with the NVs expressing wild-type fusion protein. Exhilaratingly, dual-blockade of CD47 and PD-L1 with HAC NVs exhibited excellent therapeutic efficacy and biosafety. This study provided a novel biomaterial against tumoural immune escape and more importantly an attractive biomimetic technology of protein delivery for multi-targeting therapies.

中文翻译：

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工程设计高亲和力双靶向细胞纳米囊泡以优化癌症免疫治疗

由于协同解除肿瘤免疫，双重靶向免疫检查点比单一靶向取得了更好的治疗效果。然而，大多数双重靶向策略通常是抗体依赖性的，面临着抗体的缺点，例如实体瘤渗透性差和亲和力不理想。为了应对这些挑战，我们设计了一种细胞膜，该细胞膜显示由 SIRPα 和 PD-1 变体组成的融合蛋白，即野生型分子的高亲和力共有 (HAC)，并用其制备了纳米囊泡 (NV)。通过禁用 SIRPα/CD47 和 PD-1/PD-L1 信号传导，HAC NV 分别显着保留了巨噬细胞和 T 细胞的吞噬作用和抗肿瘤作用。体内研究表明，HAC NVs比单克隆抗体具有更好的肿瘤渗透性，与表达野生型融合蛋白的NVs相比，对肿瘤细胞上CD47和PD-L1的结合亲和力更高。令人兴奋的是，用HAC NVs双重阻断CD47和PD-L1表现出优异的治疗效果和生物安全性。这项研究提供了一种对抗肿瘤免疫逃逸的新型生物材料，更重要的是，为多靶向治疗提供了一种有吸引力的蛋白质递送仿生技术。