Rouet, R. et al. J. Am. Chem. Soc. 140, 6596–6603 (2018).

A remaining bottleneck for CRISPR-mediated gene editing is cell- and tissue-specific delivery of components. Rouet et al. took advantage of cells’ highly specific cell-surface-receptor-mediated cargo uptake and fused a ligand for the asialoglycoprotein receptor (ASGPr) to Cas9. This facilitated the endocytosis of the Cas9 fusion protein specifically into hepatocytes, which exclusively express this lectin receptor. No transfection reagents were necessary, but an endosomolytic agent was needed to ensure that Cas9 escaped from the endosomes after receptor-mediated uptake. The researchers showed selective activity of Cas9 in HEPG2 cells compared with that in a control cell line, but also noted that the activity in primary hepatocytes and the application of the approach in vivo will need further optimization.