Engineered Small Extracellular Vesicles as a FGL1/PD-L1 Dual-Targeting Delivery System for Alleviating Immune Rejection

Hsiang i. Tsai, Yingyi Wu, Xiaoyan Liu, Zhanxue Xu, Longshan Liu, Changxi Wang, Huanxi Zhang, Yisheng Huang, Linglu Wang, Weixian Zhang, Dandan Su, Fahim Ullah Khan, Xiaofeng Zhu, Rongya Yang, Yuxin Pang, John E. Eriksson, Haitao Zhu, Dongqing Wang, Bo Jia, Fang Cheng*Hongbo Chen

*Corresponding author for this work

Research output: Contribution to journalArticleScientificpeer-review

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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.

Original languageEnglish
Article number2102634
JournalAdvanced Science
Volume9
Issue number3
DOIs
Publication statusPublished - 2021
MoE publication typeA1 Journal article-refereed

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