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

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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.