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Engineering circular RNA medicines

Nature Reviews Bioengineering volume 3, pages 270–287 (2025)Cite this article

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Abstract

Circular RNAs (circRNAs) are a group of RNA molecules prevalent across various organisms and tissues and characterized by a covalent loop structure. Their unique structure, lacking 5′ and 3′ ends, confers resistance to exonucleases, thereby enhancing their stability compared to linear RNAs. Since the early 2010s, the versatility of circRNAs have been highlighted in applications such as RNA aptamers, guide RNAs and, more recently, SARS-CoV-2 vaccines. Recent advances in rational design, as well as in vitro and in vivo synthesis techniques, underscore the potential for large-scale engineering and production of circRNAs, positioning them as promising candidates for stable and efficient RNA-based therapeutics with minimal immunogenicity. This Review summarizes the guiding principles behind circRNA engineering and development, with a focus on key design elements. We also provide an overview of circRNA advances in disease prevention and treatment. By emphasizing existing limitations and outlining future milestones, this Review offers a translational outlook on circRNAs as an emerging field in biomedicine.

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Fig. 1: Key components of engineered circRNAs for various purposes.
Fig. 2: In vitro generation of engineered circRNAs using ligation and the PIE system.
Fig. 3: In vivo generation of engineered circRNAs.

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Acknowledgements

This work was supported by grants from the National Key R&D Project (2021YFA1300500 and 2021YFA1302000) and the National Natural Science Foundation of China (32025009, 32130020 and 32200530).

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  1. These authors contributed equally: Xiaofei Cao, Zhengyi Cai.

Authors and Affiliations

  1. Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, Hangzhou 310024, University of Chinese Academy of Sciences, Beijing, China

    Xiaofei Cao & Fangqing Zhao

  2. Institute of Zoology, Chinese Academy of Sciences, Beijing, China

    Zhengyi Cai, Jinyang Zhang & Fangqing Zhao

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  2. Zhengyi Cai
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F.Z. conceived the project. X.C. and Z.C conducted the initial literature search. X.C., J.Z. and F.Z. wrote the manuscript synopsis. All authors contributed to writing and reviewing the manuscript.

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Correspondence to Fangqing Zhao.

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Cao, X., Cai, Z., Zhang, J. et al. Engineering circular RNA medicines. Nat Rev Bioeng 3, 270–287 (2025). https://doi.org/10.1038/s44222-024-00259-1

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