In vivo genome correction holds promise for generating durable disease cures; yet, effective stem cell editing remains challenging. In this work, we demonstrate that optimized lung-targeting lipid nanoparticles (LNPs) enable high levels of genome editing in stem cells, yielding durable responses. Intravenously administered gene-editing LNPs in activatable tdTomato mice achieved >70% lung stem cell editing, sustaining tdTomato expression in >80% of lung epithelial cells for 660 days. Addressing cystic fibrosis (CF), NG-ABE8e messenger RNA (mRNA)–sgR553X LNPs mediated >95% cystic fibrosis transmembrane conductance regulator (CFTR) DNA correction, restored CFTR function in primary patient-derived bronchial epithelial cells equivalent to Trikafta for F508del, corrected intestinal organoids and corrected R553X nonsense mutations in 50% of lung stem cells in CF mice. These findings introduce LNP-enabled tissue stem cell editing for disease-modifying genome correction.

中文翻译：

---

体内编辑肺干细胞以实现小鼠持久基因校正


体内基因组校正有望产生持久的疾病治疗方法；然而，有效的干细胞编辑仍然具有挑战性。在这项工作中，我们证明优化的肺靶向脂质纳米粒子（LNP）能够在干细胞中进行高水平的基因组编辑，从而产生持久的反应。在可激活的 tdTomato 小鼠中静脉注射基因编辑 LNP，实现了 >70% 的肺干细胞编辑，在 80% 以上的肺上皮细胞中维持 tdTomato 表达达 660 天。解决囊性纤维化 (CF)，NG-ABE8e 信使 RNA (mRNA)–sgR553X LNP 介导 >95% 囊性纤维化跨膜电导调节因子 (CFTR) DNA 校正，恢复原发性患者来源支气管上皮细胞中的 CFTR 功能，相当于 F508del 的 Trikafta，纠正了 CF 小鼠 50% 肺干细胞中的肠道类器官和 R553X 无义突变。这些发现引入了支持 LNP 的组织干细胞编辑，用于疾病修饰基因组校正。