Endosymbiotic bacteria have extracellular contractile injections systems (eCISs), syringe-like nanomachines that deliver factors into the host cells to modulate host biology. eCISs are widely present across bacterial and archaeal species, and have been recently reported to target cultured mouse cells. However, it is unclear how eCISs recognize their target cells and whether they are active in human cells. In this study, Kreitz et al. examined a specific eCIS: the Photorhabdus virulence cassette (PVC), from the entomopathogenic bacterium Photorhabdus asymbiotica. The researchers expressed PVC in Escherichia coli and used genetic recombination, microscopy and cell infection in vitro assays to demonstrate that PVC can be reprogrammed to load and deliver native and non-native proteins into different target cells. The authors discovered that PVC cell tropism is determined by the Pvc13 protein — the tail fibre of PVC that shares domain similarity with the receptor-binding tip from the tail fibre of phage T4. The interaction between Pvc13 and its target receptor determines PVC cell specificity and, thus, Pvc13 can be genetically modified to change its target specificity. PVC was not only active against cultured insect cells, but it also delivered different types of protein in human cells and in live mice.