Self-splicing RNA circularization facilitated by intact group I and II introns

Yong Shen, Bohan Li, Lei Dong, Wei Tang, Jiwu Ren, Feng Chen, Wenjuan Zheng, Ying Yu, Lu Gao and Wensheng Wei ()
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Yong Shen: Peking University
Bohan Li: Peking University
Lei Dong: Changping Laboratory
Wei Tang: Peking University
Jiwu Ren: Peking University
Feng Chen: Peking University
Wenjuan Zheng: Peking University
Ying Yu: Peking University
Lu Gao: Therorna Inc.
Wensheng Wei: Peking University

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract Circular RNA (circRNA) has gained significant attention in RNA therapeutics due to its enhanced stability and protein-coding potential. In this study, we present two in vitro RNA circularization techniques, namely Permuted Intron-Exon through Trans-splicing (PIET) and Complete self-splicing Intron for RNA Circularization (CIRC). PIET leverages the second step of group I intron splicing, offering an alternative circularization strategy. CIRC utilizes the natural, intact forms of group I and group II introns, eliminating the need for intron engineering. Compared to Permuted Intron-Exon (PIE), CIRC exhibits enhanced RNA circularization efficiency and speed under mild conditions. Using CIRC, we successfully circularize large RNA constructs encoding full-length dystrophin, a protein whose deficiency is linked to Duchenne muscular dystrophy (DMD), thus overcoming size limitations typically associated with circRNA platforms. Notably, CIRC enables the production of scarless circRNA and circRNA with minimal immunogenicity. Additionally, CIRC supports streamlined circRNA purification using ribonuclease R (RNase R) or oligo(dT)-based methods. These advancements significantly expand the potential of the circRNA platform for both research and therapeutic applications.

Date: 2025
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DOI: 10.1038/s41467-025-62607-y

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