Cryo-EM structure of a natural RNA nanocage

Xiaobin Ling (), Dmitrij Golovenko, Jianhua Gan, Jinbiao Ma (), Andrei A. Korostelev () and Wenwen Fang ()
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Xiaobin Ling: UMass Chan Medical School
Dmitrij Golovenko: UMass Chan Medical School
Jianhua Gan: Fudan University
Jinbiao Ma: Fudan University
Andrei A. Korostelev: UMass Chan Medical School
Wenwen Fang: UMass Chan Medical School

Nature, 2025, vol. 644, issue 8078, 1107-1115

Abstract: Abstract Long (>200 nucleotides) non-coding RNAs (lncRNAs) play important roles in diverse aspects of life. Over 20 classes of lncRNAs have been identified in bacteria and bacteriophages through comparative genomics analyses, but their biological functions remain largely unexplored1–3. Owing to the large sizes, the structural determinants of most lncRNAs also remain uncharacterized. Here, we report the structures of two natural RNA nanocages formed by the ROOL (rumen-originating, ornate, large) lncRNA found in bacterial and phage genomes. The cryo-electron microscopy (cryo-EM) structures at 2.9-Å resolution reveal that ROOL RNAs form an octameric nanocage with a diameter of 28 nm and an axial length of 20 nm, in which the hollow inside features poorly ordered regions. The octamer is stabilized by numerous tertiary and quaternary interactions, including triple-strand A-minors, for which we propose the term ‘A-minor staples’. The structure of an isolated ROOL monomer at 3.2-Å resolution indicates that nanocage assembly involves a strand-swapping mechanism resulting in quaternary kissing loops. Finally, we show that ROOL RNA fused to an RNA aptamer, transfer RNA or microRNA retains its structure, forming a nanocage with radially displayed cargoes. Our findings, therefore, may enable engineering of novel RNA nanocages as delivery vehicles for research and therapeutic applications.

Date: 2025
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DOI: 10.1038/s41586-025-09262-x

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