@article{a3d5f65488a04a70bc4171a77e24e1bd,
title = "Engineered Small Extracellular Vesicles as a FGL1/PD-L1 Dual-Targeting Delivery System for Alleviating Immune Rejection",
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.",
author = "Tsai, {Hsiang i.} and Yingyi Wu and Xiaoyan Liu and Zhanxue Xu and Longshan Liu and Changxi Wang and Huanxi Zhang and Yisheng Huang and Linglu Wang and Weixian Zhang and Dandan Su and Khan, {Fahim Ullah} and Xiaofeng Zhu and Rongya Yang and Yuxin Pang and Eriksson, {John E.} and Haitao Zhu and Dongqing Wang and Bo Jia and Fang Cheng and Hongbo Chen",
note = "Funding Information: H‐i T., Y.Y.W., and X.Y.L contributed equally to this work. This research was supported by the National Natural Science Foundation of China (81702750, 81970145 and 82001698); Natural Science Foundation of Guangdong Province (2020A1515011465 and 2020A151501467); Science, Technology & Innovation Commission of Shenzhen Municipality (JCYJ20180307154700308, JCYJ20170818163844015, JCYJ20180307151420045, JCYJ20190807151609464, JCYJ20200109142605909 and JCYJ20210324120007020); Sun Yat‐sen University (20ykzd17 and 20ykpy122); International Collaboration of Science and Technology of Guangdong Province (2020A0505100031); Guangdong Provincial Key Laboratory of Digestive Cancer Research (No. 2021B1212040006); The Social Development Foundation of Jiangsu Province (BE2018691) and Sigrid Jus{\'e}lius Foundation in Finland for funding the project. Funding Information: H-i T., Y.Y.W., and X.Y.L contributed equally to this work. This research was supported by the National Natural Science Foundation of China (81702750, 81970145 and 82001698); Natural Science Foundation of Guangdong Province (2020A1515011465 and 2020A151501467); Science, Technology & Innovation Commission of Shenzhen Municipality (JCYJ20180307154700308, JCYJ20170818163844015, JCYJ20180307151420045, JCYJ20190807151609464, JCYJ20200109142605909 and JCYJ20210324120007020); Sun Yat-sen University (20ykzd17 and 20ykpy122); International Collaboration of Science and Technology of Guangdong Province (2020A0505100031); Guangdong Provincial Key Laboratory of Digestive Cancer Research (No. 2021B1212040006); The Social Development?Foundation of Jiangsu Province?(BE2018691) and Sigrid Jus?lius?Foundation in Finland for funding the project. Publisher Copyright: {\textcopyright} 2021 The Authors. Advanced Science published by Wiley-VCH GmbH",
year = "2021",
doi = "10.1002/advs.202102634",
language = "English",
volume = "9",
journal = "Advanced Science",
issn = "2198-3844",
publisher = "Wiley Open Access",
number = "3",
}