Engineering circular RNA for enhanced protein production

Robert Chen, Sean K. Wang, Julia A. Belk, Laura Amaya, Zhijian Li, Angel Cardenas, Brian T. Abe, Chun Kan Chen, Paul A. Wender, Howard Y. Chang

Research output: Contribution to journalArticlepeer-review

84 Scopus citations


Circular RNAs (circRNAs) are stable and prevalent RNAs in eukaryotic cells that arise from back-splicing. Synthetic circRNAs and some endogenous circRNAs can encode proteins, raising the promise of circRNA as a platform for gene expression. In this study, we developed a systematic approach for rapid assembly and testing of features that affect protein production from synthetic circRNAs. To maximize circRNA translation, we optimized five elements: vector topology, 5′ and 3′ untranslated regions, internal ribosome entry sites and synthetic aptamers recruiting translation initiation machinery. Together, these design principles improve circRNA protein yields by several hundred-fold, provide increased translation over messenger RNA in vitro, provide more durable translation in vivo and are generalizable across multiple transgenes.

Original languageEnglish
Pages (from-to)262-272
Number of pages11
JournalNature Biotechnology
Issue number2
StatePublished - Feb 2023


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