小柯机器人

美国麻省理工学院张锋研究团队利用细菌收缩注射系统进行可编程的蛋白质输送。2023年3月29日，《自然》杂志在线发表了这项成果。

研究人员表明，一个来自昆虫致病菌Photorhabdus asymbiotica的细胞外收缩注射系统（eCIS），即Photorhabdus virulence cassette（PVC）的目标选择是由PVC尾部纤维的远端结合元件对目标受体的特定识别所介导的。此外，利用计算结构指导下的尾部纤维工程，研究人员表明PVC可以被重新编程，从而针对这些系统本身不针对的生物体，包括人类细胞和小鼠，其效率接近100%。最后，研究人员表明，PVC可以装载不同的蛋白质有效载荷，包括Cas9、碱基编辑和毒素，并可以将其功能性地送入人类细胞。这些研究结果表明，PVC是一种可编程的蛋白质递送装置，可以应用于基因治疗、癌症治疗和生物控制。

据介绍，内生细菌已经演化出复杂的输送系统，使这些生物体能够与宿主的生物学对接。其中一个例子是eCIS，它是类似注射器的大分子复合物，通过驱动刺突穿过细胞膜将蛋白质有效载荷注入真核细胞。最近，人们发现eCIS以小鼠细胞为目标，提高了这些系统被用于治疗性蛋白质递送的可能性。然而，eCIS是否能在人类细胞中发挥作用仍是未知数，而且这些系统识别目标细胞的机制也不甚明了。

附：英文原文

Title: Programmable protein delivery with a bacterial contractile injection system

Author: Kreitz, Joseph, Friedrich, Mirco J., Guru, Akash, Lash, Blake, Saito, Makoto, Macrae, Rhiannon K., Zhang, Feng

Issue&Volume: 2023-03-29

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 cells1,2,3, 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.

DOI: 10.1038/s41586-023-05870-7

Source: https://www.nature.com/articles/s41586-023-05870-7

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html