革命性的递送系统实现精确的蛋白质运输

Brain-X Pub Date : 2023-06-29 DOI:10.1002/brx2.21
Qian Zhang, Kun Zhang
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These macromolecular complexes consist of a solid tubular structure encompassed in a compressible sheath that is attached to a baseplate and sharpened by a spike protein. 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摘要

因此,在该系统应用于人类治疗之前,eCIS在体内的安全性和有效性是未来需要解决的最重要问题之一。通过开发一种灵活的重新设计系统,在广泛的应用中输送蛋白质,与eCIS相关的革命性工作可能会为人类癌症治疗和基因治疗带来更多灵感。钱章:写作——原稿。张昆:《写作——综述》;编辑。作者声明没有利益冲突。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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Revolutionary delivery system enables precise protein transportation

The capacity to transport customized proteins into certain cell types has enormous implications for life science research and disease therapy. However, challenges associated with cell targeting and protein transportation through cellular membranes still exist, necessitating the creation of complex systems that can continuously carry payload proteins into cells.1. In gene editing especially, achieving accurate targeted delivery is an intricate problem that warrants addressing. Endosymbiotic bacteria have developed complex delivery systems that enable them to interact with the host organism,2 wherein secreted contractile injection systems (CISs), which are analogous to bacteriophage tails, can be harnessed as nanodevices.3. These macromolecular complexes consist of a solid tubular structure encompassed in a compressible sheath that is attached to a baseplate and sharpened by a spike protein. It is hypothesized that payloads are packed into the lumen of the inner tube behind the spike, which upon recognition by the target cell are pushed into the target cell through the membrane via sheath contraction.4

Inspired by previous reports regarding CISs, recently, a team led by Professor Feng Zhang at the Broad Institute developed a redesigned protein delivery system; the corresponding results have been published in Nature.5 Therein, extracellular contractile injection systems (eCISs), syringe-like nanomachines mimicking bacteriophage tails that can transport payloads independently and extracellularly, served as a new tool to solve a long-standing problem, that is, how to deliver therapeutic molecules to specific types of human cells precisely and efficiently (Figure 1). The structural composition of eCISs originating from the Photorhabdus virulence cassette (PVC) is such that the tail fibers on the outside of one end recognize specific receptors on the cell surface and anchor to host cells; thus, in their study, the researchers speculated that modifying the structure of these tail fibers may enable them to recognize different cells. Given that the action and targeting mechanisms of eCISs in human cells remain a mystery, the team used AlphaFold, an artificial intelligence protein design platform that can predict protein structures from amino acid sequences, to redesign the injector of PVC to shift the targeting objective from insect cells to human cells. Cellular studies demonstrated that after modification, the syringe, carrying a variety of protein cargoes, could detect human and mouse cells. Further research on protein delivery to cultivated cells was carried out, and the modified PVC was proved to exhibit specific targeting toward epidermal growth factor receptor (EGFR) after genetic engineering.

The most promising application of the precise delivery based on such PVC-derived eCISs is the specific targeting of brain tissue and the nervous system after rationally redesigning PVC-derived eCISs via genetic engineering. The primary challenge in delivering proteins to the nervous system lies in the traversing of the blood-brain barrier (BBB) in the non-invasive and efficient manner. By pinpointing novel PVCs capable of targeting mouse cells with minimal systemic toxicity, the possibility of ideal intracranial delivery is expected. An extended tdTomato distribution representing is especially observed in the neurons of hippocampus region after intracranial injection of modified PVCs, while a negative control (Pvc10-free PVCs counterpart) fails to accumulate in the hippocampus region, which denotes that the modified PVCs have great potential for effectuating precise intracranial targeting without BBB restrictions. Particularly, the results regarding the in vivo delivery of the delicately designed eCISs, with high specificity and a lack of notable immune activity, along with their property of rapid purification from the brain, indicate their successful further application in humans.

Typically, effective treatments for central nervous system (CNS) diseases involve three inter-related factors (a) delivering payloads (e.g., drugs, proteins, or other macromolecules) across the BBB, (b) achieving effective doses of the payloads at the target site, and (c) limiting the accumulation of drugs in non-target sites. The implementation of precise delivery by eCISs not only resolves a long-standing bottleneck of gene editing but also provides a viable solution to these key challenges. The tailored eCISs have paved the way for the creation of a novel protein delivery platform and provided a direction for future research in a wide range of application landscapes. Additionally, investigating potential delivery systems similar to PVCs for a range of payloads, including RNA or DNA, may become a priority for researchers henceforth. However, given the complex nature of the human immune system, it remains to be seen whether the immunogenicity of eCISs will induce immune responses and thus reduce their delivery efficiency. Therefore, the safety and effectiveness of eCISs in vivo is one of the most important issues that need to address in the future before this system can be applied in human treatment.

By developing a flexible re-engineered system to deliver proteins across a wide range of applications, the revolutionary work related to eCISs may bring more inspiration related to cancer treatment and gene therapy in humans.

Qian Zhang: Writing—original draft. Kun Zhang: Writing—review & editing.

The authors declare no conflicts of interest.

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