Large-scale generation of functional mRNA-encapsulating exosomes via cellular nanoporation

Zhaogang Yang, Junfeng Shi, Jing Xie, Yifan Wang, Jingyao Sun, Tongzheng Liu, Yarong Zhao, Xiuting Zhao, Xinmei Wang, Yifan Ma, Veysi Malkoc, Chiling Chiang, Weiye Deng, Yuanxin Chen, Yuan Fu, Kwang J. Kwak, Yamin Fan, Chen Kang, Changcheng Yin, June RheePaul Bertani, Jose Otero, Wu Lu, Kyuson Yun, Andrew S. Lee, Wen Jiang, Lesheng Teng, Betty Y.S. Kim, L. James Lee

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Exosomes are attractive as nucleic-acid carriers because of their favourable pharmacokinetic and immunological properties and their ability to penetrate physiological barriers that are impermeable to synthetic drug-delivery vehicles. However, inserting exogenous nucleic acids, especially large messenger RNAs, into cell-secreted exosomes leads to low yields. Here we report a cellular-nanoporation method for the production of large quantities of exosomes containing therapeutic mRNAs and targeting peptides. We transfected various source cells with plasmid DNAs and stimulated the cells with a focal and transient electrical stimulus that promotes the release of exosomes carrying transcribed mRNAs and targeting peptides. Compared with bulk electroporation and other exosome-production strategies, cellular nanoporation produced up to 50-fold more exosomes and a more than 103-fold increase in exosomal mRNA transcripts, even from cells with low basal levels of exosome secretion. In orthotopic phosphatase and tensin homologue (PTEN)-deficient glioma mouse models, mRNA-containing exosomes restored tumour-suppressor function, enhanced inhibition of tumour growth and increased survival. Cellular nanoporation may enable the use of exosomes as a universal nucleic-acid carrier for applications requiring transcriptional manipulation.

Original languageEnglish (US)
Pages (from-to)69-83
Number of pages15
JournalNature Biomedical Engineering
Volume4
Issue number1
DOIs
StatePublished - Jan 1 2020

ASJC Scopus subject areas

  • Biotechnology
  • Bioengineering
  • Medicine (miscellaneous)
  • Biomedical Engineering
  • Computer Science Applications

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    Yang, Z., Shi, J., Xie, J., Wang, Y., Sun, J., Liu, T., Zhao, Y., Zhao, X., Wang, X., Ma, Y., Malkoc, V., Chiang, C., Deng, W., Chen, Y., Fu, Y., Kwak, K. J., Fan, Y., Kang, C., Yin, C., ... Lee, L. J. (2020). Large-scale generation of functional mRNA-encapsulating exosomes via cellular nanoporation. Nature Biomedical Engineering, 4(1), 69-83. https://doi.org/10.1038/s41551-019-0485-1