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<p>Circular RNA (circRNA) exhibits extended stability and enhanced protein expression, and its translational efficiency and immunogenicity can be improved through nucleoside modification and rolling circle translation (RCT). However, it remains challenging to produce protein-encoding circRNA with modified nucleosides. Here we identified a cap-independent translation enhancer (CITE) element from black beetle virus, termed BBV, which could drive the translation of nucleoside-modified RNA and RCT of engineered circRNA. In addition, we developed a system to produce ‘scarless’ circRNA via in vitro transcription (IVT). The resulting circRNA vaccine outperformed m1ψ-mRNA vaccine in inhibiting tumour growth in mice. With nucleoside modification, circRNA exhibited reduced expression of pro-inflammatory cytokines. Further, nucleoside-modified circRNA encoding glucagon-like peptide-1 (GLP-1) peptides reduced blood glucose levels with efficacy comparable to that of commercial semaglutide, and ameliorated liver damage in obese mice. Moreover, nucleoside-modified circRNA encoding myelin oligodendrocyte glycoprotein (MOG<sub>35–55</sub>) peptides induced immune tolerance and alleviated disease progression in an experimental autoimmune encephalomyelitis (EAE) murine model. Collectively, we established a nucleoside-modified circRNA platform that facilitated efficient translation with minimal immunogenicity, expanding the application scenarios of circRNA beyond vaccines.</p>

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Engineered circular RNA compatible with complete nucleoside modification and rolling circle translation through a Cap-independent translation enhancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月29日

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  • Xinyue Wang,
  • Qian Pan,
  • Jie Yin,
  • Haomeng Kou,
  • Xinyuan Liao,
  • Chi Zhang,
  • Yanyan Wang,
  • Shengnan She,
  • Ligaoyue Zhang,
  • Wanjia Wang,
  • Shan Qin,
  • Xiaohong Xia,
  • Jing Li,
  • Fei Gao,
  • Xinyang Li,
  • Yong Cao,
  • Liang Qu

摘要

Circular RNA (circRNA) exhibits extended stability and enhanced protein expression, and its translational efficiency and immunogenicity can be improved through nucleoside modification and rolling circle translation (RCT). However, it remains challenging to produce protein-encoding circRNA with modified nucleosides. Here we identified a cap-independent translation enhancer (CITE) element from black beetle virus, termed BBV, which could drive the translation of nucleoside-modified RNA and RCT of engineered circRNA. In addition, we developed a system to produce ‘scarless’ circRNA via in vitro transcription (IVT). The resulting circRNA vaccine outperformed m1ψ-mRNA vaccine in inhibiting tumour growth in mice. With nucleoside modification, circRNA exhibited reduced expression of pro-inflammatory cytokines. Further, nucleoside-modified circRNA encoding glucagon-like peptide-1 (GLP-1) peptides reduced blood glucose levels with efficacy comparable to that of commercial semaglutide, and ameliorated liver damage in obese mice. Moreover, nucleoside-modified circRNA encoding myelin oligodendrocyte glycoprotein (MOG35–55) peptides induced immune tolerance and alleviated disease progression in an experimental autoimmune encephalomyelitis (EAE) murine model. Collectively, we established a nucleoside-modified circRNA platform that facilitated efficient translation with minimal immunogenicity, expanding the application scenarios of circRNA beyond vaccines.