近日，中国科学技术大学Xucong Teng团队实现了脂质纳米颗粒递送环状ADAR招募RNA介导的TP53无义突变的RNA编辑介导校正。2025年5月21日出版的《美国化学会志》发表了这项成果。

无义突变占疾病相关突变的20%以上，无义突变是指基因序列中出现过早终止密码子（PTC），导致蛋白质截断和功能失调。然而，由于难以获得精确的靶位点和基因编辑工具的局限性，目前仍缺乏安全、有效和位点特异性的无义突变纠正方法。

研究组设计了一种环状ADAR招募RNA (Circ-arRNA)，用于体内RNA编辑介导的TP53-W53X无义突变的修复。与线性arRNA相比，Circ-RNA表现出较强的细胞内稳定性和对TP53-W53X无链突变体位点特异性校正的高效率，对旁观者碱基没有可检测到的脱靶效应。在三阴性乳腺癌TP53-W53X 4T1细胞和荷瘤motheme模型中，该团队将脂质纳米颗粒（LNPs）包裹并递送Circ-arRNA，其突变纠正效率分别为73.32%和48.48%。

Circ-arRNA LNPs能有效恢复全长p53蛋白表达及其功能活性，显著增强荷瘤小鼠对紫杉醇化疗的敏感性。该研究证明了基于LNP的环状arRNA在体内特异性修复无意义突变的安全性和有效性，突出了ADAR介导的编辑在纠正此类突变方面的巨大潜力。

附：英文原文

Title: RNA Editing-Mediated Correction of TP53 Nonsense Mutations via Lipid Nanoparticle-Delivered Circular ADAR-Recruiting RNAs

Author: Jinjin Wang, Wenjing Zhang, Shuguang Li, Wenjun Shi, Bingyu Li, Jingge Zhang, Yan Liang, Xucong Teng, Kaixiang Zhang

Issue&Volume: May 21, 2025

Abstract: Nonsense mutations account for over 20% of disease-associated mutations, which refer to the occurrence of premature termination codons (PTCs) in gene sequences, resulting in truncated and dysfunctional proteins. Nonetheless, due to poor accessibility of precise target sites and the limitations of gene editing tools, there is still a lack of safe, effective, and site-specific approach for correction of nonsense mutations. Here, we designed a circular ADAR-recruiting RNA (Circ-arRNA) for the in vivo RNA editing-mediated repair of the TP53-W53X nonsense mutation. Compared with linear arRNA, Circ-RNA demonstrates strong intracellular stability and high efficiency for site-specific correction of the TP53-W53X nonsense mutant, with no detectable off-target effects on bystander bases. In triple-negative breast cancer TP53-W53X 4T1 cells and tumor-bearing mouse models, we used lipid nanoparticles (LNPs) to encapsulate and deliver Circ-arRNA, which achieved mutation correction efficiencies of 73.32 and 48.48%, respectively. Furthermore, Circ-arRNA LNPs effectively restored full-length p53 protein expression and its functional activity, significantly enhancing the sensitivity of tumor-bearing mice to paclitaxel chemotherapy. Our research demonstrated the safety and efficacy of LNP-based circular arRNA for specifically the repair of nonsense mutations in vivo, highlighting the immense potential of ADAR-mediated editing for correcting such mutations.

DOI: 10.1021/jacs.4c17920

Source: https://pubs.acs.org/doi/abs/10.1021/jacs.4c17920