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

doi:10.1002/advs.202102634

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

Biochemistry and Cell Biology

Research output: Contribution to journal › Article › Scientific › peer-review

55 Citations (Scopus)

266 Downloads (Pure)

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 language	English
Article number	2102634
Journal	Advanced Science
Volume	9
Issue number	3
DOIs	https://doi.org/10.1002/advs.202102634
Publication status	Published - 2021
MoE publication type	A1 Journal article-refereed

Funding

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 Jusélius Foundation in Finland for funding the project. 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.

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10.1002/advs.202102634

Advanced Science - 2021 - Tsai - Engineered Small Extracellular Vesicles as a FGL1 PD‐L1 Dual‐Targeting Delivery System forFinal published version, 5.6 MBLicence: CC BY

https://urn.fi/URN:NBN:fi-fe2022021619293

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Tsai, H. I., Wu, Y., Liu, X., Xu, Z., Liu, L., Wang, C., Zhang, H., Huang, Y., Wang, L., Zhang, W., Su, D., Khan, F. U., Zhu, X., Yang, R., Pang, Y., Eriksson, J. E., Zhu, H., Wang, D., Jia, B., ... Chen, H. (2021). Engineered Small Extracellular Vesicles as a FGL1/PD-L1 Dual-Targeting Delivery System for Alleviating Immune Rejection. Advanced Science, 9(3), Article 2102634. https://doi.org/10.1002/advs.202102634

@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",

}

Tsai, HI, Wu, Y, Liu, X, Xu, Z, Liu, L, Wang, C, Zhang, H, Huang, Y, Wang, L, Zhang, W, Su, D, Khan, FU, Zhu, X, Yang, R, Pang, Y, Eriksson, JE, Zhu, H, Wang, D, Jia, B, Cheng, F & Chen, H 2021, 'Engineered Small Extracellular Vesicles as a FGL1/PD-L1 Dual-Targeting Delivery System for Alleviating Immune Rejection', Advanced Science, vol. 9, no. 3, 2102634. https://doi.org/10.1002/advs.202102634

TY - JOUR

T1 - Engineered Small Extracellular Vesicles as a FGL1/PD-L1 Dual-Targeting Delivery System for Alleviating Immune Rejection

AU - Tsai, Hsiang i.

AU - Wu, Yingyi

AU - Liu, Xiaoyan

AU - Xu, Zhanxue

AU - Liu, Longshan

AU - Wang, Changxi

AU - Zhang, Huanxi

AU - Huang, Yisheng

AU - Wang, Linglu

AU - Zhang, Weixian

AU - Su, Dandan

AU - Khan, Fahim Ullah

AU - Zhu, Xiaofeng

AU - Yang, Rongya

AU - Pang, Yuxin

AU - Eriksson, John E.

AU - Zhu, Haitao

AU - Wang, Dongqing

AU - Jia, Bo

AU - Cheng, Fang

AU - Chen, Hongbo

N1 - 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 Jusélius 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: © 2021 The Authors. Advanced Science published by Wiley-VCH GmbH

PY - 2021

Y1 - 2021

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85118482489

U2 - 10.1002/advs.202102634

DO - 10.1002/advs.202102634

M3 - Article

AN - SCOPUS:85118482489

SN - 2198-3844

VL - 9

JO - Advanced Science

JF - Advanced Science

IS - 3

M1 - 2102634

ER -

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

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