Although gene editing is beginning to achieve clinical acceptance as an intervention for some genetic diseases, difficulties remain. Challenges include efficient editing of cells directly in an organism rather than ex vivo and long-term persistence of the edits, which requires targeting the relevant stem cells. Sun et al. designed lipid nanoparticles for delivering gene-editing reagents and optimized them to deliver these reagents to all lung cell types, including stem cells (see the Perspective by Bulcaen and Carlon). The authors then tested their approach in patient-derived cells and in a mouse model of cystic fibrosis, demonstrating that they could achieve therapeutically relevant editing lasting for up to a year. —Yevgeniya Nusinovich

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.