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.