{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T00:01:00Z","timestamp":1788912060069,"version":"build-2803163510"},"reference-count":43,"publisher":"Springer Science and Business Media LLC","issue":"6","license":[{"start":{"date-parts":[[2025,9,18]],"date-time":"2025-09-18T00:00:00Z","timestamp":1758153600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,9,18]],"date-time":"2025-09-18T00:00:00Z","timestamp":1758153600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Chem Biol"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Endogenous uridine-rich small nuclear RNAs (U snRNAs) form RNA\u2013protein complexes to process eukaryotic pre-mRNA into mRNA. Previous studies have demonstrated programmable U snRNA guide-targeted exon inclusion and exclusion. Here we investigated whether snRNAs can also enhance RNA base editing over state-of-the-art RNA-targeting technologies in human cells. Compared with adenosine deaminase acting on RNA (ADAR)-recruiting circular RNAs, we find that guided A&gt;I snRNAs consistently increase adenosine-to-inosine editing for higher exon count genes, perturb substantially fewer off-target genes and localize more persistently to the nucleus where ADAR is expressed. A&gt;I snRNAs also more efficiently edit long noncoding RNAs and pre-mRNA 3\u2032 splice sites to promote splicing changes. Lastly, snRNA\u2013H\/ACA box snoRNA fusions (U&gt;\u03a8 snRNAs) increase targeted RNA pseudouridylation without DKC1 overexpression, facilitating improved\n                    <jats:italic>CFTR<\/jats:italic>\n                    rescue from nonsense-mediated mRNA decay in a cystic fibrosis human bronchial epithelial cell model. Our results advance the endogenous protein-mediated RNA base editing toolbox and RNA-targeting technologies to treat genetic diseases.\n                  <\/jats:p>","DOI":"10.1038\/s41589-025-02026-8","type":"journal-article","created":{"date-parts":[[2025,9,18]],"date-time":"2025-09-18T09:03:28Z","timestamp":1758186208000},"page":"995-1003","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Enhancing RNA base editing on mammalian transcripts with small nuclear RNAs"],"prefix":"10.1038","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4677-1682","authenticated-orcid":false,"given":"Aaron A.","family":"Smargon","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5627-3380","authenticated-orcid":false,"given":"Deepak","family":"Pant","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trent A.","family":"Gomberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Fagre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sofia","family":"Glynne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johnathan","family":"Nguyen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jack T.","family":"Naritomi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2807-9657","authenticated-orcid":false,"given":"Wendy V.","family":"Gilbert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0799-6037","authenticated-orcid":false,"given":"Gene W.","family":"Yeo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,9,18]]},"reference":[{"key":"2026_CR1","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1038\/s41589-023-01531-y","volume":"20","author":"J Song","year":"2024","unstructured":"Song, J., Zhuang, Y. & Yi, C. Programmable RNA base editing via targeted modifications. Nat. Chem. Biol. 20, 277\u2013290 (2024).","journal-title":"Nat. Chem. Biol."},{"key":"2026_CR2","doi-asserted-by":"publisher","first-page":"1037","DOI":"10.1002\/humu.20763","volume":"29","author":"M Mort","year":"2008","unstructured":"Mort, M., Ivanov, D., Cooper, D. N. & Chuzhanova, N. A. A meta-analysis of nonsense mutations causing human genetic disease. Hum. Mutat. 29, 1037\u20131047 (2008).","journal-title":"Hum. Mutat."},{"key":"2026_CR3","doi-asserted-by":"publisher","first-page":"6549","DOI":"10.1093\/nar\/gkw533","volume":"44","author":"MA Havens","year":"2016","unstructured":"Havens, M. A. & Hastings, M. L. Splice-switching antisense oligonucleotides as therapeutic drugs. Nucleic Acids Res. 44, 6549\u20136563 (2016).","journal-title":"Nucleic Acids Res."},{"key":"2026_CR4","doi-asserted-by":"publisher","first-page":"467","DOI":"10.1038\/nm0496-467","volume":"2","author":"M Howard","year":"1996","unstructured":"Howard, M., Frizzell, R. A. & Bedwell, D. M. Aminoglycoside antibiotics restore CFTR function by overcoming premature stop mutations. Nat. Med. 2, 467\u2013469 (1996).","journal-title":"Nat. Med."},{"key":"2026_CR5","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1038\/nature05756","volume":"447","author":"EM Welch","year":"2007","unstructured":"Welch, E. M. et al. PTC124 targets genetic disorders caused by nonsense mutations. Nature 447, 87\u201391 (2007).","journal-title":"Nature"},{"key":"2026_CR6","doi-asserted-by":"publisher","first-page":"842","DOI":"10.1038\/s41586-023-06133-1","volume":"618","author":"S Albers","year":"2023","unstructured":"Albers, S. et al. Engineered tRNAs suppress nonsense mutations in cells and in vivo. Nature 618, 842\u2013848 (2023).","journal-title":"Nature"},{"key":"2026_CR7","doi-asserted-by":"publisher","first-page":"e1641","DOI":"10.1002\/wrna.1641","volume":"12","author":"JJ Porter","year":"2021","unstructured":"Porter, J. J., Heil, C. S. & Lueck, J. D. Therapeutic promise of engineered nonsense suppressor tRNAs. Wiley Interdiscip. Rev. RNA 12, e1641 (2021).","journal-title":"Wiley Interdiscip. Rev. RNA"},{"key":"2026_CR8","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1038\/nrm.2015.4","volume":"17","author":"K Nishikura","year":"2016","unstructured":"Nishikura, K. A-to-I editing of coding and non-coding RNAs by ADARs. Nat. Rev. Mol. Cell Biol. 17, 83\u201396 (2016).","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"2026_CR9","doi-asserted-by":"publisher","first-page":"759","DOI":"10.1038\/s41587-021-01105-0","volume":"40","author":"P Reautschnig","year":"2022","unstructured":"Reautschnig, P. et al. CLUSTER guide RNAs enable precise and efficient RNA editing with endogenous ADAR enzymes in vivo. Nat. Biotechnol. 40, 759\u2013768 (2022).","journal-title":"Nat. Biotechnol."},{"key":"2026_CR10","doi-asserted-by":"publisher","first-page":"938","DOI":"10.1038\/s41587-021-01171-4","volume":"40","author":"D Katrekar","year":"2022","unstructured":"Katrekar, D. et al. Efficient in vitro and in vivo RNA editing via recruitment of endogenous ADARs using circular guide RNAs. Nat. Biotechnol. 40, 938\u2013945 (2022).","journal-title":"Nat. Biotechnol."},{"key":"2026_CR11","doi-asserted-by":"publisher","first-page":"946","DOI":"10.1038\/s41587-021-01180-3","volume":"40","author":"Z Yi","year":"2022","unstructured":"Yi, Z. et al. Engineered circular ADAR-recruiting RNAs increase the efficiency and fidelity of RNA editing in vitro and in vivo. Nat. Biotechnol. 40, 946\u2013955 (2022).","journal-title":"Nat. Biotechnol."},{"key":"2026_CR12","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms1324","volume":"2","author":"JM Eggington","year":"2011","unstructured":"Eggington, J. M., Greene, T. & Bass, B. L. Predicting sites of ADAR editing in double-stranded RNA. Nat. Commun. 2, 319 (2011).","journal-title":"Nat. Commun."},{"key":"2026_CR13","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1146\/annurev-genet-112618-043830","volume":"54","author":"EK Borchardt","year":"2020","unstructured":"Borchardt, E. K., Martinez, N. M. & Gilbert, W. V. Regulation and function of RNA pseudouridylation in human cells. Annu. Rev. Genet. 54, 309\u2013336 (2020).","journal-title":"Annu. Rev. Genet."},{"key":"2026_CR14","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1016\/j.tig.2018.11.005","volume":"35","author":"J Kufel","year":"2019","unstructured":"Kufel, J. & Grzechnik, P. Small nucleolar RNAs tell a different tale. Trends Genet. 35, 104\u2013117 (2019).","journal-title":"Trends Genet."},{"key":"2026_CR15","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1038\/nature10165","volume":"474","author":"J Karijolich","year":"2011","unstructured":"Karijolich, J. & Yu, Y. T. Converting nonsense codons into sense codons by targeted pseudouridylation. Nature 474, 395\u2013398 (2011).","journal-title":"Nature"},{"key":"2026_CR16","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1016\/j.molcel.2022.11.011","volume":"83","author":"J Song","year":"2023","unstructured":"Song, J. et al. CRISPR-free, programmable RNA pseudouridylation to suppress premature termination codons. Mol. Cell 83, 139\u2013155 (2023).","journal-title":"Mol. Cell"},{"key":"2026_CR17","doi-asserted-by":"publisher","first-page":"637","DOI":"10.1016\/j.molcel.2023.01.009","volume":"83","author":"H Adachi","year":"2023","unstructured":"Adachi, H. et al. Targeted pseudouridylation: an approach for suppressing nonsense mutations in disease genes. Mol. Cell 83, 637\u2013651 (2023).","journal-title":"Mol. Cell"},{"key":"2026_CR18","doi-asserted-by":"publisher","first-page":"819","DOI":"10.1126\/science.1231143","volume":"339","author":"L Cong","year":"2013","unstructured":"Cong, L. et al. Multiplex genome engineering using CRISPR\/Cas systems. Science 339, 819\u2013823 (2013).","journal-title":"Science"},{"key":"2026_CR19","doi-asserted-by":"publisher","first-page":"823","DOI":"10.1126\/science.1232033","volume":"339","author":"P Mali","year":"2013","unstructured":"Mali, P. et al. RNA-guided human genome engineering via Cas9. Science 339, 823\u2013826 (2013).","journal-title":"Science"},{"key":"2026_CR20","doi-asserted-by":"publisher","first-page":"e3321","DOI":"10.1002\/jgm.3321","volume":"23","author":"A Gadgil","year":"2021","unstructured":"Gadgil, A. & Raczynska, K. D. U7 snRNA: a tool for gene therapy. J. Gene Med. 23, e3321 (2021).","journal-title":"J. Gene Med."},{"key":"2026_CR21","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms11168","volume":"7","author":"ME Rogalska","year":"2016","unstructured":"Rogalska, M. E. et al. Therapeutic activity of modified U1 core spliceosomal particles. Nat. Commun. 7, 11168 (2016).","journal-title":"Nat. Commun."},{"key":"2026_CR22","doi-asserted-by":"publisher","first-page":"6571","DOI":"10.1073\/pnas.111153798","volume":"98","author":"O Raitskin","year":"2001","unstructured":"Raitskin, O., Cho, D. S., Sperling, J., Nishikura, K. & Sperling, R. RNA editing activity is associated with splicing factors in lnRNP particles: the nuclear pre-mRNA processing machinery. Proc. Natl Acad. Sci. USA 98, 6571\u20136576 (2001).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2026_CR23","doi-asserted-by":"publisher","first-page":"2765","DOI":"10.1016\/j.molcel.2024.06.008","volume":"84","author":"R Ietswaart","year":"2024","unstructured":"Ietswaart, R. et al. Genome-wide quantification of RNA flow across subcellular compartments reveals determinants of the mammalian transcript life cycle. Mol. Cell 84, 2765\u20132784 (2024).","journal-title":"Mol. Cell"},{"key":"2026_CR24","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1002\/humu.21426","volume":"32","author":"KM Flanigan","year":"2011","unstructured":"Flanigan, K. M. et al. Nonsense mutation-associated Becker muscular dystrophy: interplay between exon definition and splicing regulatory elements within the DMD gene. Hum. Mutat. 32, 299\u2013308 (2011).","journal-title":"Hum. Mutat."},{"key":"2026_CR25","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8","volume":"15","author":"MI Love","year":"2014","unstructured":"Love, M. I., Huber, W. & Anders, S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, 550 (2014).","journal-title":"Genome Biol."},{"key":"2026_CR26","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-09234-6","volume":"10","author":"Y Zhou","year":"2019","unstructured":"Zhou, Y. et al. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat. Commun. 10, 1523 (2019).","journal-title":"Nat. Commun."},{"key":"2026_CR27","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-36585-y","volume":"14","author":"J Vaquero-Garcia","year":"2023","unstructured":"Vaquero-Garcia, J. et al. RNA splicing analysis using heterogeneous and large RNA-seq datasets. Nat. Commun. 14, 1230 (2023).","journal-title":"Nat. Commun."},{"key":"2026_CR28","doi-asserted-by":"publisher","first-page":"e28625","DOI":"10.7554\/eLife.28625","volume":"6","author":"SN Deffit","year":"2017","unstructured":"Deffit, S. N. et al. The C.\u2009elegans neural editome reveals an ADAR target mRNA required for proper chemotaxis. eLife 6, e28625 (2017).","journal-title":"eLife"},{"key":"2026_CR29","doi-asserted-by":"publisher","first-page":"6482","DOI":"10.1093\/nar\/gkn658","volume":"36","author":"SB Patel","year":"2008","unstructured":"Patel, S. B. & Bellini, M. The assembly of a spliceosomal small nuclear ribonucleoprotein particle. Nucleic Acids Res. 36, 6482\u20136493 (2008).","journal-title":"Nucleic Acids Res."},{"key":"2026_CR30","doi-asserted-by":"publisher","first-page":"212","DOI":"10.1038\/s41586-024-07060-5","volume":"627","author":"LH Ngo","year":"2024","unstructured":"Ngo, L. H. et al. Nuclear export of circular RNA. Nature 627, 212\u2013220 (2024).","journal-title":"Nature"},{"key":"2026_CR31","doi-asserted-by":"publisher","first-page":"812","DOI":"10.1101\/gr.231209.117","volume":"28","author":"YE Hsiao","year":"2018","unstructured":"Hsiao, Y. E. et al. RNA editing in nascent RNA affects pre-mRNA splicing. Genome Res. 28, 812\u2013823 (2018).","journal-title":"Genome Res."},{"key":"2026_CR32","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1038\/s41421-019-0109-7","volume":"5","author":"J Winter","year":"2019","unstructured":"Winter, J. et al. Targeted exon skipping with AAV-mediated split adenine base editors. Cell Discov. 5, 41 (2019).","journal-title":"Cell Discov."},{"key":"2026_CR33","doi-asserted-by":"publisher","first-page":"344","DOI":"10.1038\/s41587-022-01505-w","volume":"41","author":"Q Dai","year":"2023","unstructured":"Dai, Q. et al. Quantitative sequencing using BID-seq uncovers abundant pseudouridines in mammalian mRNA at base resolution. Nat. Biotechnol. 41, 344\u2013354 (2023).","journal-title":"Nat. Biotechnol."},{"key":"2026_CR34","doi-asserted-by":"publisher","first-page":"eadg1805","DOI":"10.1126\/sciadv.adg1805","volume":"9","author":"C Pederiva","year":"2023","unstructured":"Pederiva, C. et al. Control of protein synthesis through mRNA pseudouridylation by dyskerin. Sci. Adv. 9, eadg1805 (2023).","journal-title":"Sci. Adv."},{"key":"2026_CR35","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1038\/nrm3742","volume":"15","author":"AG Matera","year":"2014","unstructured":"Matera, A. G. & Wang, Z. A day in the life of the spliceosome. Nat. Rev. Mol. Cell Biol. 15, 108\u2013121 (2014).","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"2026_CR36","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-42252-z","volume":"14","author":"Y Cao","year":"2023","unstructured":"Cao, Y. et al. RNA-based translation activators for targeted gene upregulation. Nat. Commun. 14, 6827 (2023).","journal-title":"Nat. Commun."},{"key":"2026_CR37","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-025-02628-6","author":"Y Sun","year":"2025","unstructured":"Sun, Y. et al. Improved RNA base editing with guide RNAs mimicking highly edited endogenous ADAR substrates. Nat. Biotechnol. https:\/\/doi.org\/10.1038\/s41587-025-02628-6 (2025).","journal-title":"Nat. Biotechnol."},{"key":"2026_CR38","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-025-60155-z","volume":"16","author":"SM Byrne","year":"2025","unstructured":"Byrne, S. M. et al. An engineered U7 small nuclear RNA scaffold greatly increases ADAR-mediated programmable RNA base editing. Nat. Commun. 16, 4860 (2025).","journal-title":"Nat. Commun."},{"key":"2026_CR39","doi-asserted-by":"publisher","first-page":"208","DOI":"10.1038\/s41594-018-0030-z","volume":"25","author":"J Choi","year":"2018","unstructured":"Choi, J. et al. 2\u2032-O-methylation in mRNA disrupts tRNA decoding during translation elongation. Nat. Struct. Mol. Biol. 25, 208\u2013216 (2018).","journal-title":"Nat. Struct. Mol. Biol."},{"key":"2026_CR40","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-11375-7","volume":"10","author":"BA Elliott","year":"2019","unstructured":"Elliott, B. A. et al. Modification of messenger RNA by 2\u2032-O-methylation regulates gene expression in vivo. Nat. Commun. 10, 3401 (2019).","journal-title":"Nat. Commun."},{"key":"2026_CR41","doi-asserted-by":"publisher","first-page":"2797","DOI":"10.1016\/j.molcel.2022.05.016","volume":"82","author":"D Arango","year":"2022","unstructured":"Arango, D. et al. Direct epitranscriptomic regulation of mammalian translation initiation through N4-acetylcytidine. Mol. Cell 82, 2797\u20132814 (2022).","journal-title":"Mol. Cell"},{"key":"2026_CR42","first-page":"1582","volume":"28","author":"S Thalalla Gamage","year":"2022","unstructured":"Thalalla Gamage, S. et al. Antisense pairing and SNORD13 structure guide RNA cytidine acetylation. RNA 28, 1582\u20131596 (2022).","journal-title":"RNA"},{"key":"2026_CR43","doi-asserted-by":"publisher","unstructured":"Smargon, A. A. & Yee, B. YeoLab\/Yeo_RNA_base_editing: v1.0. Zenodo https:\/\/doi.org\/10.5281\/zenodo.16755321 (2025).","DOI":"10.5281\/zenodo.16755321"}],"container-title":["Nature Chemical Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41589-025-02026-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41589-025-02026-8","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41589-025-02026-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T03:03:43Z","timestamp":1780283023000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41589-025-02026-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,18]]},"references-count":43,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2026,6]]}},"alternative-id":["2026"],"URL":"https:\/\/doi.org\/10.1038\/s41589-025-02026-8","relation":{},"ISSN":["1552-4450","1552-4469"],"issn-type":[{"value":"1552-4450","type":"print"},{"value":"1552-4469","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,18]]},"assertion":[{"value":"11 June 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 August 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 September 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"G.W.Y. and A.A.S. have filed for patent application number PCT\/US2025\/032791 related to this work. G.W.Y. is a cofounder, member of the board of directors, scientific advisory board member, equity holder and paid consultant for Eclipse BioInnovations. G.W.Y.\u2019s interests have been reviewed and approved by the University of California, San Diego in accordance with its conflict-of-interest policies. W.V.G. is a cofounder and scientific advisory board member for Cloverleaf Bio. W.V.G.\u2019s interests have been reviewed and approved by Yale University in accordance with its conflict-of-interest policies. The other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}