Journal
COMMUNICATIONS BIOLOGY
Volume 5, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s42003-022-03987-5
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Funding
- Wellcome Trust
- Royal Society through a Sir Henry Dale Fellowship [215453/Z/19/Z]
- Wellcome Trust [215453/Z/19/Z] Funding Source: Wellcome Trust
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Non-coding RNAs (ncRNAs) offer a wealth of therapeutic targets for a range of diseases, but their secondary structures and sequence similarities pose challenges for specific knockdown. Researchers have engineered a series of artificial oligonucleotide enzymes (XNAzymes) composed of a modified nucleic acid that can specifically or preferentially cleave individual ncRNA members under physiological conditions. These XNAzymes can self-assemble into a stable nanostructure and target cancer-associated microRNAs, offering a potential platform for precise knockdown of specific non-coding RNAs with reduced off-target effects compared to other nucleic acid technologies.
Non-coding RNAs (ncRNAs) offer a wealth of therapeutic targets for a range of diseases. However, secondary structures and high similarity within sequence families make specific knockdown challenging. Here, we engineer a series of artificial oligonucleotide enzymes (XNAzymes) composed of 2'-deoxy-2'-fluoro-beta-D-arabino nucleic acid (FANA) that specifically or preferentially cleave individual ncRNA family members under quasi-physiological conditions, including members of the classic microRNA cluster miR-17 similar to 92 (oncomiR-1) and the Y RNA hY5. We demonstrate self-assembly of three anti-miR XNAzymes into a biostable catalytic XNA nanostructure, which targets the cancer-associated microRNAs miR-17, miR-20a and miR-21. Our results provide a starting point for the development of XNAzymes as a platform technology for precision knockdown of specific non-coding RNAs, with the potential to reduce off-target effects compared with other nucleic acid technologies.
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