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 University, and Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, Zhejiang Province, 310003, P. R. China.
Zhejiang University-University of Edinburgh Institute, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, 310003, P. R. China.
Adv Sci (Weinh). 2022 Nov;9(31):e2202633. doi: 10.1002/advs.202202633. Epub 2022 Sep 8.
Direct contact of membrane molecules and cytokine interactions orchestrate immune homeostasis. However, overcoming the threshold of distance and velocity barriers, and achieving adhesion mediated immune interaction remain difficult. Here, inspired by the natural chemotaxis of regulatory T cells, multifunctionalized FOXP3 genetic engineered extracellular vesicles, termed Foe-TEVs, are designed, which display with adhesive molecules, regulatory cytokines, and coinhibitory contact molecules involving CTLA-4 and PD-1, by limited exogenous gene transduction. Foe-TEVs effectively adhere to the tubular, endothelial, and glomerular regions of allogeneic injury in the renal allograft, mitigating cell death in situ and chronic fibrosis transition. Remarkably, transcript engineering reverses the tracking velocity of vesicles to a retained phenotype and enhanced arrest coefficient by a factor of 2.16, directly interacting and attenuating excessive allosensitization kinetics in adaptive lymphoid organs. In murine allogeneic transplantation, immune adhesive Foe-TEVs alleviate pathological responses, restore renal function with well ordered ultrastructure and improved glomerular filtration rate, and prolong the survival period of the recipient from 30.16 to 92.81 days, demonstrating that the delivery of extracellular vesicles, genetically engineered for immune adhesive, is a promising strategy for the treatment of graft rejection.
膜分子的直接接触和细胞因子相互作用协调免疫稳态。然而，克服距离和速度障碍的阈值，并实现介导免疫相互作用的黏附仍然具有挑战性。在这里，受调节性 T 细胞自然趋化性的启发，设计了多功能化的 FOXP3 基因工程细胞外囊泡，称为 Foe-TEVs，其通过有限的外源性基因转导显示涉及 CTLA-4 和 PD-1 的黏附分子、调节细胞因子和共抑制接触分子。Foe-TEVs 有效地黏附于同种异体损伤的管状、内皮和肾小球区域，减轻原位细胞死亡和慢性纤维化转化。值得注意的是，转录工程将囊泡的追踪速度逆转至保留表型，并通过因子 2.16 增强了阻滞系数，直接相互作用并减弱了适应性淋巴器官中过度同种致敏的动力学。在小鼠同种异体移植中，免疫黏附的 Foe-TEVs 减轻了病理性反应，恢复了肾功能，具有有序的超微结构和改善的肾小球滤过率，并将受者的存活期从 30.16 天延长至 92.81 天，表明用于免疫黏附的细胞外囊泡的递送是治疗移植物排斥的一种有前途的策略。
