Kidney Disease Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Key Laboratory of Kidney Disease Prevention and Control Technology, National Key Clinical Department of Kidney Diseases. Institute of Nephrology, Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Zhejiang University, Hangzhou 310003, Zhejiang Province, P. R. China.
Department of Radiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, P. R. China.
ACS Appl Mater Interfaces. 2023 Jul 26;15(29):34588-34606. doi: 10.1021/acsami.3c06885. Epub 2023 Jul 17.
Disturbance of single-cell transcriptional heterogeneity is an inevitable consequence of persistent donor-specific antibody (DSA) production and allosensitization. However, identifying and efficiently clearing allospecific antibody repertoires to restore single-cell transcriptional profiles remain challenging. Here, inspired by the high affinity of natural bacterial proteins for antibodies, a genetic engineered membrane-coated nanoparticle termed as DSA trapper by the engineering chimeric gene of protein A/G with phosphatidylserine ligands for macrophage phagocytosis was reported. It has been shown that DSA trappers adsorbed alloreactive antibodies with high saturation and activated the heterophagic clearance of antibody complexes, alleviating IgG deposition and complement activation. Remarkably, DSA trappers increased the endothelial protective lineages by 8.39-fold, reversed the highly biased cytotoxicity, and promoted the proliferative profiles of Treg cells, directly providing an obligate immune tolerant niche for single-cell heterogeneity restoration. In the mice of allogeneic transplantation, the DSA trapper spared endothelial from inflammatory degenerative rosette, improved the glomerular filtration rate, and prolonged the survival of allogeneic mice from 23.6 to 78.3 days. In general, by identifying the lineage characteristics of rejection-related antibodies, the chimeric engineered DSA trapper realized immunoadsorption and further phagocytosis of alloantibody complexes to restore the single-cell genetic architecture of the allograft, offering a promising prospect for the treatment of alloantibody-mediated immune injury.
单细胞转录异质性的紊乱是持续产生供体特异性抗体 (DSA) 和同种致敏的必然结果。然而，识别和有效地清除同种特异性抗体库以恢复单细胞转录谱仍然具有挑战性。在这里，受天然细菌蛋白与抗体具有高亲和力的启发，报告了一种经过基因工程改造的膜包覆纳米颗粒，称为 DSA 捕集器，其通过与磷脂酰丝氨酸配体融合的蛋白 A/G 的工程嵌合基因进行工程改造，以用于巨噬细胞吞噬作用。已经表明，DSA 捕集器以高饱和度吸附同种反应性抗体，并激活抗体复合物的异噬清除，从而减轻 IgG 沉积和补体激活。值得注意的是，DSA 捕集器使内皮保护性谱系增加了 8.39 倍，逆转了高度偏向的细胞毒性，并促进了 Treg 细胞的增殖谱，直接为单细胞异质性恢复提供了必需的免疫耐受生态位。在同种异体移植的小鼠中，DSA 捕集器使内皮免于炎症退行性玫瑰花结，提高了肾小球滤过率，并将同种异体小鼠的存活时间从 23.6 天延长至 78.3 天。总的来说，通过鉴定与排斥相关的抗体的谱系特征，嵌合工程 DSA 捕集器实现了同种异体抗体复合物的免疫吸附和进一步吞噬，从而恢复了移植物的单细胞遗传结构，为治疗同种抗体介导的免疫损伤提供了有前途的前景。
