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

Shiyan Dong, Xuan Liu, Ye Bi, Yifan Wang, Abin Antony, DaeYong Lee, Kristin Huntoon, Seongdong Jeong, Yifan Ma, Xuefeng Li, Weiye Deng, Benjamin R. Schrank, Adam J. Grippin, JongHoon 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 () and Wen Jiang ()
Additional contact information
Shiyan Dong: Jilin University
Xuan Liu: The University of Texas MD Anderson Cancer Center
Ye Bi: Changchun University of Chinese Medicine
Yifan Wang: The University of Texas MD Anderson Cancer Center
Abin Antony: The University of Texas MD Anderson Cancer Center
DaeYong Lee: The University of Texas MD Anderson Cancer Center
Kristin Huntoon: The University of Texas MD Anderson Cancer Center
Seongdong Jeong: The University of Texas MD Anderson Cancer Center
Yifan Ma: The Ohio State University
Xuefeng Li: The University of Texas MD Anderson Cancer Center
Weiye Deng: The University of Texas MD Anderson Cancer Center
Benjamin R. Schrank: The University of Texas MD Anderson Cancer Center
Adam J. Grippin: The University of Texas MD Anderson Cancer Center
JongHoon Ha: The University of Texas MD Anderson Cancer Center
Minjeong Kang: The University of Texas MD Anderson Cancer Center
Mengyu Chang: The University of Texas MD Anderson Cancer Center
Yarong Zhao: Jilin University
Rongze Sun: Jilin University
Xiangshi Sun: Jilin University
Jie Yang: Jilin University
Jiayi Chen: Jilin University
Sarah K. Tang: The University of Texas MD Anderson Cancer Center
L. James Lee: The Ohio State University
Andrew S. Lee: Shenzhen Bay Laboratory
Lirong Teng: Jilin University
Shengnian Wang: Louisiana Tech University
Lesheng Teng: Jilin University
Betty Y. S. Kim: The University of Texas MD Anderson Cancer Center
Zhaogang Yang: Jilin University
Wen Jiang: The University of Texas MD Anderson Cancer Center

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-42365-5

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