EPSRC New Horizons 2021: Engineering synthetic synapses between artificial and biological cells.

EPSRC New Horizo​​ns 2021：人工细胞和生物细胞之间的工程合成突触。

• 批准号: EP/X018903/1
• 负责人: Lorenzo Di Michele
• 金额: $ 25.78万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FX018903%2F1
• 关键词: EPSRC; New; Horizons; 2021; Engineering

Cells from the immune system have the ability to target and kill other undesirable cells, for instance cancer cells. A key mechanism underpinning recognition and killing is the formation of an "immune synapse" - a region of close contact between the membranes of the target and immune cell. Among other functions, the immune synapse enables localised and selective delivery of toxic compounds from the immune cell to the target cell, leading to death of the target. Besides playing a critical role in the natural immune response, immune cells known as T cells form the basis of modern cancer immunotherapies, where T cells extracted from the patients are genetically engineered to help them target the specific cancer the patient has, before being reintroduced in the body. These therapies have proven very successful, particularly for some types of blood cancer, but their broad application is hindered by the technical challenges associated to performing genetic engineering on patient cells, which results in very high costs for healthcare systems.Inspired by the action of immune cells here we propose to construct "artificial immune cells" able to selectively and controllably form "synthetic immune synapses", which target cancer cells and inject them with anti-cancer drugs. If successful, these synthetic cell-like agents could underpin novel therapies that represent a more scalable and sustainable alternative to live-cell immunotherapies.With the term "artificial cell" we describe a broad variety of fully synthetic micromachines constructed from scratch, borrowing building blocks from biology (proteins, lipid membranes) and complementing them with synthetic nanostructures. Artificial cells can serve as model systems to better understand basic biological phenomena but are often designed to target specific problems in healthcare, such as diagnostics and therapeutics. Compared to live biological cells, artificial cells are easier to program, cheaper to manufacture and carry fewer risks and ethical concerns. However, artificial cells are still unable to replicate some of the highly complex behaviours of biological cells, including the ability to target and kill cancer cells. With the proposed research project, we plan to tackle this bottleneck through a combination of protein engineering and DNA nanotechnology, which we will use to construct new molecular machines that mediate immune synapse formation. Protein engineering takes natural proteins as the starting point, and then modifies them to impart new functionalities. DNA nanotechnology, in turn, utilises synthetic nucleic acid molecules like molecular Lego bricks, to construct functional nanoscale machines with precisely controlled shape and functionality. Synthetic capsules (vesicles) formed from lipid bilayers and mimicking the membrane of biological cells will constitute the chassis of the artificial cells, which will be decorated with the synapse forming protein/DNA machinery and encapsulate the therapeutic agent to be injected in the cancer cell.For this initial proof-of-concept study we will construct and optimise the protein and DNA machinery and equip the artificial cells with it, before testing the so-formed agents on model cancer cells in vitro, using "test tube" experiments that mimic the conditions found in the body. The information we gather on the robustness of the artificial cells and their ability to target cancer cells selectively and effectively will inform subsequent translational studies in which we will test the artificial therapeutic agents in vivo, starting with animal models.

免疫系统的细胞具有靶向和杀死其他不良细胞（例如癌细胞）的能力。支撑识别和杀戮的关键机制是形成“免疫突触” - 靶标和免疫细胞膜之间紧密接触的区域。除其他功能外，免疫突触可使有毒化合物从免疫细胞到靶细胞的局部和选择性递送，从而导致靶细胞死亡。除了在自然免疫反应中起关键作用外，被称为T细胞的免疫细胞构成了现代癌症免疫疗法的基础，在该癌症中，从患者中提取的T细胞进行了基因工程，以帮助他们靶向患者患者的特定癌症，然后再重新引入体内。 These therapies have proven very successful, particularly for some types of blood cancer, but their broad application is hindered by the technical challenges associated to performing genetic engineering on patient cells, which results in very high costs for healthcare systems.Inspired by the action of immune cells here we propose to construct "artificial immune cells" able to selectively and controllably form "synthetic immune synapses", which target cancer cells and inject them with anti-cancer drugs.如果成功的话，这些类似于合成细胞的剂可以支持新型疗法，代表了实时细胞免疫疗法的一种更可扩展，更可持续的替代品。我们用“人造细胞”一词描述了从SCRATCH构建的各种完全合成的微机器，从生物学（蛋白质，Lipid Membranes）和与之互补的NAN NAN NAN NAN NAN NAN NAN NAN NAN NAN NAN NAN NANSTONTY。人造细胞可以用作模型系统，以更好地了解基本的生物学现象，但通常旨在针对医疗保健中的特定问题，例如诊断和治疗剂。与实时生物细胞相比，人造细胞更容易编程，更便宜的生产和更少的风险和道德问题。但是，人造细胞仍然无法复制生物细胞的某些高度复杂行为，包括靶向和杀死癌细胞的能力。通过拟议的研究项目，我们计划通过蛋白质工程和DNA纳米技术的结合来解决这种瓶颈，我们将使用它们来构建介导免疫突触形成的新分子机器。蛋白质工程将天然蛋白作为起点，然后将其修改以赋予新功能。反过来，DNA纳米技术依次利用合成核酸分子（如分子乐高积木）来构建具有精确控制形状和功能的功能性纳米级机器。由脂质双层形成并模仿生物细胞的膜形成的合成胶囊（海囊）将构成人造细胞的底盘，人造细胞的底盘将用突触形成蛋白质/DNA机械的突触装饰，并将治疗剂封装在此最初的癌细胞中，并在癌症中注射并在癌症中构建和优化，我们将构建蛋白质，并在癌症中构建蛋白质，并在癌症中构建蛋白质。它在使用模仿体内发现的“试管”实验的“试管”实验之前，先在体外测试所谓癌细胞上的所谓剂之前。我们收集的有关人造细胞鲁棒性的信息及其有效地靶向癌细胞的能力将为随后的翻译研究提供信息，我们将从动物模型开始，在体内测试人造治疗剂。