Sculpting synthetic cells: a new approach to designing synthetic compartments

The team of Lorenzo Di Michele at the University of Cambridge in the UK, with the support of collaborators from University College London, has successfully met the challenge of developing a device that mimics the structural complexity of cells and is capable of hosting multiple activities. Their approach, based on DNA nanostructures, has the advantage of being simple and reliable, and constitutes a promising tool not only for the design of synthetic cell prototypes, but also for their future deployment in industry.

Compartments in phase-separated binary condensates. Chem 2023 93347-3364 DOI: (10.1016/j.chempr.2023.10.004) Copyright © 2023 Layla Malouf, Diana A. Tanase, Giacomo Fabrini, Ryan A. Brady, Miguel Paez-Perez, Adrian Leathers, Michael J. Booth, Lorenzo Di Michele 

Just as modern homes are divided into several spaces enabling people to carry out certain activities more efficiently (cooking in the kitchen, washing in the bathroom), living cells can also exhibit such structural complexity. The compartmentalisation of cells enables them to create specialised environments for specific cellular functions. Many researchers around the world are working to recreate such structural and functional complexity, by developing different approaches.

DNA nanotechnology to reproduce the complex and compartmentalised interior of cells

DNA nanotechnology is the speciality of the DiMichele Lab, a research group led by Lorenzo Di Michele at the University of Cambridge in the UK. While DNA can be considered as a molecule encoding all the information necessary for the proper functioning of living organisms, the field of DNA nanotechnology takes this molecule out of its biological context and uses it to assemble DNA nanostructures that can then be used for different purposes. In a new publication in Chem, published in November 2023, the team presented a new method based on DNA nanotechnology to create a device that mimics the structural and functional complexity of cells.

Layla Malouf

Layla Malouf, PhD student in Lorenzo’s team and first author of this work, explained: “We used amphiphilic DNA nanostructures to build our devices. Amphiphilic means that our DNA is both lipophilic and hydrophilic, i.e. it has an affinity for both lipids and water, like soap. Nanostructures with these characteristics can spontaneously assemble to form large droplet-like aggregates, that we can refer to as ‘condensates’.”

“Our group had already done some work to identify how the properties of amphiphilic DNA nanostructures influence their ability to form condensates. In this study, we focused on the combination of two populations of amphiphilic DNA nanostructures. When mixed, they can form condensates with two distinct internal regions, which act as compartments. We thought that these more complex architectures would be ideal scaffolds for building synthetic cells.”

Cell-like devices can host multiple cellular activities

With the support of group members at Imperial College London and collaborators at University College London, Layla identified the drivers and design principles for building compartmentalised structures. She then supplemented the devices with an outer lipid layer, a pseudo-membrane as Layla calls it, and showed that these cell-like devices could host functions similar to those of living cells, for example, the ability to synthesise RNA and to disassemble, a reaction similar to cell death.

Phase-separated binary condensates surrounded by a lipid shell (red). Chem 2023 93347-3364 DOI: (10.1016/j.chempr.2023.10.004) Copyright © 2023 Layla Malouf, Diana A. Tanase, Giacomo Fabrini, Ryan A. Brady, Miguel Paez-Perez, Adrian Leathers, Michael J. Booth, Lorenzo Di Michele 

A simple but robust approach, of interest for both research and industrial applications

The team believes that its approach can help in the construction of multifunctional synthetic cells. “We have provided researchers with a simple but robust toolbox,” added Layla. “Apart from the pseudo-membrane, which was added at a later stage, all the components required for the structure and compartmentalised functionalities were added in the first stage. In addition, these condensates require only a simple thermal process to form, without the need for expensive equipment.”

She concluded: “I think that the simplicity of preparing these devices could make them appealing to industry in the future. This is particularly true for high-added value applications, where limited quantities of the synthetic cells would be required, for instance in diagnostics and therapeutics.”

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Sculpting DNA to Build the Future of Synthetic Cells by the University of Cambridge

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