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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

6 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 languageEnglish
Article number6610
JournalNature Communications
Volume14
Issue number1
DOIs
StatePublished - Dec 2023

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