Programmable protein delivery with a bacterial contractile injection system

发光杆菌属 生物信息学 生物 细胞生物学 细胞外 药物输送 计算生物学 细菌 纳米技术 基因 生物化学 材料科学 遗传学
作者
Joseph Kreitz,Mirco Friedrich,Akash Guru,Blake Lash,Makoto Saito,Rhiannon K. Macrae,Feng Zhang
出处
期刊:Nature [Springer Nature]
卷期号:616 (7956): 357-364 被引量:60
标识
DOI:10.1038/s41586-023-05870-7
摘要

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 cells 1–3 , 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.
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