Bacterial strains and genes within the microbiome are increasingly being linked to human health. Exploring these interactions in detail could open the door to microbiome-based therapies. However, modifying specific bacterial populations in vivo without killing them has not yet been achieved. Writing in Nature, Brödel et al. address this challenge by engineering a phage-derived particle to deliver a base editor to gut bacteria in living mice.

The authors engineered multiple chimeric variants of λ phage tail tip proteins to target several Escherichia coli receptors in the gut. This delivery vehicle was loaded with a plasmid carrying a base editor targeting specific E. coli genes and optimized to prevent replication inside bacteria. Administering a single dose of a base editor targeting the β-lactamase gene in a model E. coli strain in the mouse gut resulted in 93% editing efficiency within 8 hours. The phage vector could be adapted to different natural pathogenic isolates, achieving efficient delivery to two additional E. coli strains and one Klebsiella pneumoniae strain. The system also successfully edited the csgA gene, which is implicated in neurodegenerative and autoimmune diseases, in a pathogenic E. coli strain in the mouse gut, with around 70% efficiency maintained for at least three weeks.

微生物组内的细菌菌株和基因越来越多地与人类健康联系在一起。详细探索这些相互作用可以为基于微生物组的疗法打开大门。然而，在体内改变特定细菌群体而不杀死它们尚未实现。 Brödel 等人在《自然》杂志上撰文。通过设计一种噬菌体衍生颗粒，将碱基编辑器传递给活体小鼠的肠道细菌来应对这一挑战。

作者设计了 λ 噬菌体尾尖蛋白的多个嵌合变体，以靶向肠道中的几种大肠杆菌受体。该运载工具装载了带有针对特定大肠杆菌基因的碱基编辑器的质粒，并经过优化以防止在细菌内复制。在小鼠肠道模型大肠杆菌菌株中施用单剂量的针对 β-内酰胺酶基因的碱基编辑器，可在 8 小时内实现 93% 的编辑效率。该噬菌体载体可以适应不同的天然致病分离株，实现对另外两种大肠杆菌菌株和一种肺炎克雷伯菌菌株的有效递送。该系统还成功编辑了小鼠肠道致病性大肠杆菌菌株中的csgA基因，该基因与神经退行性疾病和自身免疫性疾病有关，并且效率保持在 70% 左右至少三周。