Engineered Small Extracellular Vesicles as a FGL1/PD‐L1 Dual‐Targeting Delivery System for Alleviating Immune Rejection. Issue 3 (5th November 2021)

• Record Type: Journal Article
• Authors: Tsai, Hsiang‐i; Wu, Yingyi; Liu, Xiaoyan; Xu, Zhanxue; Liu, Longshan; Wang, Changxi; Zhang, Huanxi; Huang, Yisheng; Wang, Linglu; Zhang, Weixian; Su, Dandan; Khan, Fahim Ullah; Zhu, Xiaofeng; Yang, Rongya; Pang, Yuxin; Eriksson, John E.; Zhu, Haitao; Wang, Dongqing; Jia, Bo; Cheng, Fang; Chen, Hongbo
• Is Part Of: Advanced science. Volume 9:Issue 3(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-11-05
• Subjects: FGL1 -- Immunological rejection -- Immunosuppressant -- PD‐L1 -- Small extracellular vesicles; Science -- Periodicals; 505
• DOI: 10.1002/advs.202102634
• Languages: English
• ISSNs: 2198-3844

Abstract

Abstract: There is an urgent need for developing new immunosuppressive agents due to the toxicity of long‐term use of broad immunosuppressive agents after organ transplantation. Comprehensive sample analysis revealed dysregulation of FGL1/LAG‐3 and PD‐L1/PD‐1 immune checkpoints in allogeneic heart transplantation mice and clinical kidney transplant patients. In order to enhance these two immunosuppressive signal axes, a bioengineering strategy is developed to simultaneously display FGL1/PD‐L1 (FP) on the surface of small extracellular vesicles (sEVs). Among various cell sources, FP sEVs derived from mesenchymal stem cells (MSCs) not only enriches FGL1/PD‐L1 expression but also maintain the immunomodulatory properties of unmodified MSC sEVs. Next, it is confirmed that FGL1 and PD‐L1 on sEVs are specifically bound to their receptors, LAG‐3 and PD‐1 on target cells. Importantly, FP sEVs significantly inhibite T cell activation and proliferation in vitro and a heart allograft model. Furthermore, FP sEVs encapsulated with low‐dose FK506 (FP sEVs@FK506) exert stronger effects on inhibiting T cell proliferation, reducing CD8 + T cell density and cytokine production in the spleens and heart grafts, inducing regulatory T cells in lymph nodes, and extending graft survival. Taken together, dual‐targeting sEVs have the potential to boost the immune inhibitory signalings in synergy and slow down transplant rejection. Abstract : MSC‐derived FGL1/PD‐L1 sEVs encapsulated in FK506 exhibited a strong ability to inhibit T cell activation and proliferation, and also induced Tregs in organ recipient mice. An experimental basis for a novel intervention strategy is provided that leverages the function of target delivery sEVs to synergistically enhance two immunosuppression axes and reestablish immune tolerance, ultimately promoting organ acceptance.