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<p>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 (<Emphasis Type="Underline">R</Emphasis>NA <Emphasis Type="Underline">e</Emphasis>diting with <Emphasis Type="Underline">co</Emphasis>n<Emphasis Type="Underline">d</Emphasis>itionally stable and <Emphasis Type="Underline">e</Emphasis>nhanced 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 <i>FUS</i> mutation and installs a therapeutic mutation to <i>Angptl3</i> 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.</p>

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Target-stabilized base editors enable robust high-fidelity RNA editing

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月25日

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  • Taian Liu,
  • Yunping Lin,
  • Qiwei Liu,
  • Wenhui Liao,
  • Yunyi Lin,
  • Yujing Zhang,
  • Jianqing Zhang,
  • Wenhua Cao,
  • Lixin Yang,
  • Zexuan Hong,
  • Zhonghua Lu

摘要

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.