Abstract
RNA base editing using engineered deaminases represents a powerful tool to correct mutations at the RNA level. However, widespread off-target effects, primarily arising from dissociated free deaminases, remain a significant challenge. Here, we devise the RECODE (RNA editing with conditionally stable and enhanced ADAR1 deaminase variants) system, which employs designer degron-tagged ADAR1 deaminase (ADAR1d) with guide RNA (gRNA)-regulated stability. By promoting degradation of gRNA-unbound ADAR1d, RECODE markedly reduces transcriptome-wide edits while maintaining high on-target efficacy. Engineering gRNA for target RNA-induced conformational switching confines ADAR1d stabilization to intended editing sites, further enhancing editing precision. With structure-guided rational engineering of ADAR1d, RECODE efficiently corrects an Amyotrophic Lateral Sclerosis-relevant FUS mutation and installs a therapeutic mutation to Angptl3 in vivo, which mitigate FUS mislocalization to neuronal axons and lower plasma lipids, respectively. These findings establish RECODE as a highly stringent and efficient RNA editing technology and underscore a general principle for enhancing the specificity of RNA-guided protein effectors.
Data availability
The data supporting the results in this study are available within the paper and its supplementary information. Raw RNA-seq data for Fig. 3j and Fig. 5h can be accessed at the National Center for Biotechnology Information (NCBI) BioProject under the accession code: PRJNA1393754 or The Sequence Read Archive (SRA) under the accession code: SRP658796. Source data are provided in this paper.
Code availability
No original code was generated in this study.
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Acknowledgements
We thank Dr. Chunshan Deng, Dr. Yinqing Li, and members of the Lu laboratory for helpful discussions and comments. This research was supported by Shenzhen Medical Research Fund grants B2504002 (Z.L.), B2402029 (Z.L.), and B2302053 (Z.L.), Strategic Priority Research Program of the Chinese Academy of Sciences grant XDB0930000 (Z.L.), National Natural Science Foundation of China grants 32400927 (Z.H.) and 82327805 (Z.L.), Shenzhen Science and Technology Innovation Commission grant KQTD20210811090117032 (Z.L.), China Postdoctoral Science Foundation grant 2023M743681 (Z.H.), and Guangdong Basic and Applied Research Foundation grant 2023A1515110864 (Z.H.).
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T.L. and Z.L. conceived the project. T.L., Yunping Lin, Q.L., W.L., Yunyi Lin, Y.Z., J.Z., and W.C. developed methods and performed experiments. T.L., Yunping Lin, Q.L., L.Y., and Z.H. analyzed data. Z.L. supervised the project. T.L., Yunping Lin, Z.H., and Z.L. wrote the manuscript. All authors read and approved the manuscript.
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T.L., Z.L., Yunping Lin, and Z.H. are co-inventors on a provisional patent that is being filed for this technology (PCT/CN2025/098018). The remaining authors declare no competing interests.
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Liu, T., Lin, Y., Liu, Q. et al. Target-stabilized base editors enable robust high-fidelity RNA editing. Nat Commun (2026). https://doi.org/10.1038/s41467-026-69835-w
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DOI: https://doi.org/10.1038/s41467-026-69835-w
