Programmable protein delivery with a bacterial contractile injection system
Name
s41586-023-05870-7.pdf
Description
Published version
Size
40.84 MB
Format
Adobe PDF
Checksum (MD5)
17b9a5ea8e435a6ff9f3767c49028d6a
Author(s)
Kreitz, Joseph
Friedrich, Mirco J
Guru, Akash
Lash, Blake
Saito, Makoto
Macrae, Rhiannon K
Zhang, Feng
Date Issued
March 29, 2023
Journal
Nature
Publisher
Springer Science and Business Media LLC
Citation
Kreitz, Joseph, Friedrich, Mirco J, Guru, Akash, Lash, Blake, Saito, Makoto et al. 2023. "Programmable protein delivery with a bacterial contractile injection system." Nature.
Version
Final published version
Abstract
AbstractEndosymbiotic bacteria have evolved intricate delivery systems that enable these organisms to interface with host biology. One example, the extracellular contractile injection systems (eCISs), are syringe-like macromolecular complexes that inject protein payloads into eukaryotic cells by driving a spike through the cellular membrane. Recently, eCISs have been found to target mouse cells1–3, raising the possibility that these systems could be harnessed for therapeutic protein delivery. However, whether eCISs can function in human cells remains unknown, and the mechanism by which these systems recognize target cells is poorly understood. Here we show that target selection by the Photorhabdus virulence cassette (PVC)—an eCIS from the entomopathogenic bacterium Photorhabdus asymbiotica—is mediated by specific recognition of a target receptor by a distal binding element of the PVC tail fibre. Furthermore, using in silico structure-guided engineering of the tail fibre, we show that PVCs can be reprogrammed to target organisms not natively targeted by these systems—including human cells and mice—with efficiencies approaching 100%. Finally, we show that PVCs can load diverse protein payloads, including Cas9, base editors and toxins, and can functionally deliver them into human cells. Our results demonstrate that PVCs are programmable protein delivery devices with possible applications in gene therapy, cancer therapy and biocontrol.
MIT Department
Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences
Terms of Use
Creative Commons Attribution
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1038/s41586-023-05870-7
