Programmable protein delivery with a bacterial contractile injection system

Joseph Kreitz, Mirco J. Friedrich, Akash Guru, Blake Lash, Makoto Saito, Rhiannon K. Macrae and Feng Zhang ()
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Joseph Kreitz: Howard Hughes Medical Institute
Mirco J. Friedrich: Howard Hughes Medical Institute
Akash Guru: Howard Hughes Medical Institute
Blake Lash: Howard Hughes Medical Institute
Makoto Saito: Howard Hughes Medical Institute
Rhiannon K. Macrae: Howard Hughes Medical Institute
Feng Zhang: Howard Hughes Medical Institute

Nature, 2023, vol. 616, issue 7956, 357-364

Abstract: Abstract Endosymbiotic 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.

Date: 2023
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DOI: 10.1038/s41586-023-05870-7

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