Mechano-responsive synthetic cells to engineer the immune response

越来越多的观点认为，生物系统的功能取决于其机械特性和产生机械力的能力。免疫细胞也是如此，它的内力产生机制，即细胞骨架，对它们的功能至关重要。与此同时，对免疫系统的更好理解为其作为治疗药物的用途带来了巨大的希望，从而设计我们自己的免疫系统将能够更有效地治疗癌症。实现这一潜力依赖于加速我们对机械力如何调节免疫细胞功能的理解。在拟议的工作中，我们将开发基于水凝胶微球的合成细胞，模拟抗原呈递细胞的物理特性。通过与免疫细胞的相互作用，合成细胞可以系统地告知特定的物理特性，如硬度，如何调节免疫细胞功能。此外，我们将设计我们的合成细胞，使它们能够报告免疫细胞产生的力，并通过生物化学信号对力的施加作出反应。通过这种方式，免疫细胞功能固有的力产生可以被利用来释放信号分子，这些信号分子反过来可以影响免疫细胞功能。通过设计这种机械诱导的反馈回路，我们将研究在肿瘤微环境中设计免疫细胞功能的潜力。因此，拟议的工作将为免疫细胞的功能如何依赖于机械力提供关键见解，并提供一种利用机械调节来增强和调整免疫细胞功能以实现新疗法的方法。

There is a growing perspective whereby the function of biological systems is dependent on their mechanical properties and their ability to generate mechanical forces. This is true of immune cells, whose internal force generating machinery; the cell cytoskeleton, is essential to their function. At the same time, an improved understanding of the immune system holds huge promise towards its use as a therapeutic, whereby engineering our own immune system will enable more effective treatment of cancers. Realising this potential relies on accelerating our understanding of how mechanical forces regulate immune cell function. In the proposed work, we will develop synthetic cells based on hydrogel microspheres that mimic the physical properties of antigen presenting cells. Via their interaction with immune cells, the synthetic cells can systemically informing how specific physical properties, such as stiffness, regulate immune cell function. Furthermore, we will engineer our synthetic cells such that they are able to report on forces generated by the immune cells and respond to the application of force via biochemical signalling. In this way, force generation intrinsic to immune cell function can be harnessed to release signalling molecules that can in turn influence immune cell function. By engineering such mechanically induced feedback loops, we will investigate the potential of engineering immune cell function within the tumour micro-environment. Consequently, the proposed work will provide key insights into how the function of immune cells depends on mechanical forces, and provide a means of exploiting mechano-regulation to augment and tune immune cell function toward novel therapies.