Nature biomedical engineeringJun 29, 2026

Designed circular RNA that works with full nucleoside changes and can produce proteins without a cap using a special enhancer

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Jun 30, 2026

Abstract

Nucleoside-modified circular RNA (circRNA) encoding glucagon-like peptide-1 (GLP-1) peptides reduced blood glucose levels with efficacy comparable to that of commercial semaglutide.

CircRNA exhibits extended stability and enhanced protein expression.
A cap-independent translation enhancer from black beetle virus (BBV) may improve the translation of nucleoside-modified RNA.
Development of a 'scarless' circRNA production system via in vitro transcription (IVT) was achieved.
Nucleoside-modified circRNA reduced the expression of pro-inflammatory cytokines.
CircRNA vaccines outperformed m1ψ-mRNA vaccines in inhibiting tumor growth in mice.
CircRNA encoding myelin oligodendrocyte glycoprotein (MOG_35-55) peptides may induce immune tolerance and alleviate disease progression in a mouse model.

Simplified

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_35-55) 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.

Full Text

Full text is available at the source.

View Full Text ↗

Featured in

mRNA TechnologyIssue #44

Light-activated lipid nanoparticles spin their way out of cellular traps to boost cancer vaccine results

↗

Designed circular RNA that works with full nucleoside changes and can produce proteins without a cap using a special enhancer

Abstract

Full Text

Featured in

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the mrna technology brief