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Engineering circular RNA for potent and stable translation in eukaryotic cells

Author

Listed:
  • R. Alexander Wesselhoeft

    (Massachusetts Institute of Technology
    Massachusetts Institute of Technology)

  • Piotr S. Kowalski

    (Massachusetts Institute of Technology)

  • Daniel G. Anderson

    (Massachusetts Institute of Technology
    Massachusetts Institute of Technology
    Massachusetts Institute of Technology
    Massachusetts Institute of Technology)

Abstract

Messenger RNA (mRNA) has broad potential for application in biological systems. However, one fundamental limitation to its use is its relatively short half-life in biological systems. Here we develop exogenous circular RNA (circRNA) to extend the duration of protein expression from full-length RNA messages. First, we engineer a self-splicing intron to efficiently circularize a wide range of RNAs up to 5 kb in length in vitro by rationally designing ubiquitous accessory sequences that aid in splicing. We maximize translation of functional protein from these circRNAs in eukaryotic cells, and we find that engineered circRNA purified by high performance liquid chromatography displays exceptional protein production qualities in terms of both quantity of protein produced and stability of production. This study pioneers the use of exogenous circRNA for robust and stable protein expression in eukaryotic cells and demonstrates that circRNA is a promising alternative to linear mRNA.

Suggested Citation

  • R. Alexander Wesselhoeft & Piotr S. Kowalski & Daniel G. Anderson, 2018. "Engineering circular RNA for potent and stable translation in eukaryotic cells," Nature Communications, Nature, vol. 9(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-05096-6
    DOI: 10.1038/s41467-018-05096-6
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    Cited by:

    1. Hui Ning & Gan Liu & Lei Li & Qiang Liu & Huiya Huang & Zhen Xie, 2023. "Rational design of microRNA-responsive switch for programmable translational control in mammalian cells," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    2. Chunwei Zheng & Bin Liu & Xiaolong Dong & Nicholas Gaston & Erik J. Sontheimer & Wen Xue, 2023. "Template-jumping prime editing enables large insertion and exon rewriting in vivo," Nature Communications, Nature, vol. 14(1), pages 1-9, December.
    3. Chan-I Su & Zih-Shiuan Chuang & Chi-Ting Shie & Hsin-I Wang & Yu-Ting Kao & Chia-Yi Yu, 2024. "A cis-acting ligase ribozyme generates circular RNA in vitro for ectopic protein functioning," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    4. Xinglong Liu & Zhengfeng Li & Xiaoxia Li & Weixuan Wu & Huadong Jiang & Yufen Zheng & Junjie Zhou & Xianmiao Ye & Junnan Lu & Wei Wang & Lei Yu & Yiping Li & Linbing Qu & Jianhua Wang & Feng Li & Ling, 2024. "A single-dose circular RNA vaccine prevents Zika virus infection without enhancing dengue severity in mice," Nature Communications, Nature, vol. 15(1), pages 1-19, December.

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