Adaptive design of mRNA-loaded extracellular vesicles for targeted immunotherapy of cancer

Shiyan Dong; Xuan Liu; Ye Bi; Yifan Wang; Abin Antony; Dae Yong Lee; Kristin Huntoon; Seongdong Jeong; Yifan Ma; Xuefeng Li; Weiye Deng; Benjamin R. Schrank; Adam J. Grippin; Jong Hoon Ha; Minjeong Kang; Mengyu Chang; Yarong Zhao; Rongze Sun; Xiangshi Sun; Jie Yang; Jiayi Chen; Sarah K. Tang; L. James Lee; Andrew S. Lee; Lirong Teng; Shengnian Wang; Lesheng Teng; Betty Y.S. Kim; Zhaogang Yang; Wen Jiang

doi:10.1038/s41467-023-42365-5

Adaptive design of mRNA-loaded extracellular vesicles for targeted immunotherapy of cancer

Shiyan Dong, Xuan Liu, Ye Bi, Yifan Wang, Abin Antony, Dae Yong Lee, Kristin Huntoon, Seongdong Jeong, Yifan Ma, Xuefeng Li, Weiye Deng, Benjamin R. Schrank, Adam J. Grippin, Jong Hoon Ha, Minjeong Kang, Mengyu Chang, Yarong Zhao, Rongze Sun, Xiangshi Sun, Jie YangJiayi Chen, Sarah K. Tang, L. James Lee, Andrew S. Lee, Lirong Teng, Shengnian Wang, Lesheng Teng, Betty Y.S. Kim, Zhaogang Yang, Wen Jiang

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

7 Scopus citations

Abstract

The recent success of mRNA therapeutics against pathogenic infections has increased interest in their use for other human diseases including cancer. However, the precise delivery of the genetic cargo to cells and tissues of interest remains challenging. Here, we show an adaptive strategy that enables the docking of different targeting ligands onto the surface of mRNA-loaded small extracellular vesicles (sEVs). This is achieved by using a microfluidic electroporation approach in which a combination of nano- and milli-second pulses produces large amounts of IFN-γ mRNA-loaded sEVs with CD64 overexpressed on their surface. The CD64 molecule serves as an adaptor to dock targeting ligands, such as anti-CD71 and anti-programmed cell death-ligand 1 (PD-L1) antibodies. The resulting immunogenic sEVs (imsEV) preferentially target glioblastoma cells and generate potent antitumour activities in vivo, including against tumours intrinsically resistant to immunotherapy. Together, these results provide an adaptive approach to engineering mRNA-loaded sEVs with targeting functionality and pave the way for their adoption in cancer immunotherapy applications.

Original language	English (US)
Article number	6610
Journal	Nature communications
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41467-023-42365-5
State	Published - Dec 2023

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Dong, S., Liu, X., Bi, Y., Wang, Y., Antony, A., Lee, D. Y., Huntoon, K., Jeong, S., Ma, Y., Li, X., Deng, W., Schrank, B. R., Grippin, A. J., Ha, J. H., Kang, M., Chang, M., Zhao, Y., Sun, R., Sun, X., ... Jiang, W. (2023). Adaptive design of mRNA-loaded extracellular vesicles for targeted immunotherapy of cancer. Nature communications, 14(1), Article 6610. https://doi.org/10.1038/s41467-023-42365-5

Dong, S, Liu, X, Bi, Y, Wang, Y, Antony, A, Lee, DY, Huntoon, K, Jeong, S, Ma, Y, Li, X, Deng, W, Schrank, BR, Grippin, AJ, Ha, JH, Kang, M, Chang, M, Zhao, Y, Sun, R, Sun, X, Yang, J, Chen, J, Tang, SK, Lee, LJ, Lee, AS, Teng, L, Wang, S, Teng, L, Kim, BYS, Yang, Z & Jiang, W 2023, 'Adaptive design of mRNA-loaded extracellular vesicles for targeted immunotherapy of cancer', Nature communications, vol. 14, no. 1, 6610. https://doi.org/10.1038/s41467-023-42365-5

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abstract = "The recent success of mRNA therapeutics against pathogenic infections has increased interest in their use for other human diseases including cancer. However, the precise delivery of the genetic cargo to cells and tissues of interest remains challenging. Here, we show an adaptive strategy that enables the docking of different targeting ligands onto the surface of mRNA-loaded small extracellular vesicles (sEVs). This is achieved by using a microfluidic electroporation approach in which a combination of nano- and milli-second pulses produces large amounts of IFN-γ mRNA-loaded sEVs with CD64 overexpressed on their surface. The CD64 molecule serves as an adaptor to dock targeting ligands, such as anti-CD71 and anti-programmed cell death-ligand 1 (PD-L1) antibodies. The resulting immunogenic sEVs (imsEV) preferentially target glioblastoma cells and generate potent antitumour activities in vivo, including against tumours intrinsically resistant to immunotherapy. Together, these results provide an adaptive approach to engineering mRNA-loaded sEVs with targeting functionality and pave the way for their adoption in cancer immunotherapy applications.",

author = "Shiyan Dong and Xuan Liu and Ye Bi and Yifan Wang and Abin Antony and Lee, {Dae Yong} and Kristin Huntoon and Seongdong Jeong and Yifan Ma and Xuefeng Li and Weiye Deng and Schrank, {Benjamin R.} and Grippin, {Adam J.} and Ha, {Jong Hoon} and Minjeong Kang and Mengyu Chang and Yarong Zhao and Rongze Sun and Xiangshi Sun and Jie Yang and Jiayi Chen and Tang, {Sarah K.} and Lee, {L. James} and Lee, {Andrew S.} and Lirong Teng and Shengnian Wang and Lesheng Teng and Kim, {Betty Y.S.} and Zhaogang Yang and Wen Jiang",

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AU - Huntoon, Kristin

AU - Jeong, Seongdong

AU - Ma, Yifan

AU - Li, Xuefeng

AU - Deng, Weiye

AU - Schrank, Benjamin R.

AU - Grippin, Adam J.

AU - Ha, Jong Hoon

AU - Kang, Minjeong

AU - Chang, Mengyu

AU - Zhao, Yarong

AU - Sun, Rongze

AU - Sun, Xiangshi

AU - Yang, Jie

AU - Chen, Jiayi

AU - Tang, Sarah K.

AU - Lee, L. James

AU - Lee, Andrew S.

AU - Teng, Lirong

AU - Wang, Shengnian

AU - Teng, Lesheng

AU - Kim, Betty Y.S.

AU - Yang, Zhaogang

AU - Jiang, Wen

PY - 2023/12

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N2 - The recent success of mRNA therapeutics against pathogenic infections has increased interest in their use for other human diseases including cancer. However, the precise delivery of the genetic cargo to cells and tissues of interest remains challenging. Here, we show an adaptive strategy that enables the docking of different targeting ligands onto the surface of mRNA-loaded small extracellular vesicles (sEVs). This is achieved by using a microfluidic electroporation approach in which a combination of nano- and milli-second pulses produces large amounts of IFN-γ mRNA-loaded sEVs with CD64 overexpressed on their surface. The CD64 molecule serves as an adaptor to dock targeting ligands, such as anti-CD71 and anti-programmed cell death-ligand 1 (PD-L1) antibodies. The resulting immunogenic sEVs (imsEV) preferentially target glioblastoma cells and generate potent antitumour activities in vivo, including against tumours intrinsically resistant to immunotherapy. Together, these results provide an adaptive approach to engineering mRNA-loaded sEVs with targeting functionality and pave the way for their adoption in cancer immunotherapy applications.

AB - The recent success of mRNA therapeutics against pathogenic infections has increased interest in their use for other human diseases including cancer. However, the precise delivery of the genetic cargo to cells and tissues of interest remains challenging. Here, we show an adaptive strategy that enables the docking of different targeting ligands onto the surface of mRNA-loaded small extracellular vesicles (sEVs). This is achieved by using a microfluidic electroporation approach in which a combination of nano- and milli-second pulses produces large amounts of IFN-γ mRNA-loaded sEVs with CD64 overexpressed on their surface. The CD64 molecule serves as an adaptor to dock targeting ligands, such as anti-CD71 and anti-programmed cell death-ligand 1 (PD-L1) antibodies. The resulting immunogenic sEVs (imsEV) preferentially target glioblastoma cells and generate potent antitumour activities in vivo, including against tumours intrinsically resistant to immunotherapy. Together, these results provide an adaptive approach to engineering mRNA-loaded sEVs with targeting functionality and pave the way for their adoption in cancer immunotherapy applications.

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Adaptive design of mRNA-loaded extracellular vesicles for targeted immunotherapy of cancer

Abstract

ASJC Scopus subject areas

MD Anderson CCSG core facilities

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