A promising DNA-origami tool for the design of synthetic cells

Scientists from the UK and Belgium recently teamed up to design DOLAs. These structures made of DNA have been coupled to synthetic membranes, giving membranes the ability to control the organization of their lipids. Thanks to DOLAs, these now-active membranes have great potential, as they could help researchers reproduce some of the essential functionalities of living cells and advance research on synthetic cells.

The Di Michele Lab unleashes the potential of synthetic membranes

Cell membranes consist of a lipid bilayer that surrounds the cell and separates it from the external environment. In a paper published in the Journal of the American Society in May 2023, Lorenzo Di Michele and his colleagues focused on mimicking a specific mechanism taking place on the membrane.

Stabilized lipid domains. Source: DNA-Origami Line-Actants Control Domain Organization and Fission in Synthetic Membranes Roger Rubio-Sánchez, Bortolo Matteo Mognetti, Pietro Cicuta, and Lorenzo Di Michele Journal of the American Chemical Society 2023 145 (20), 11265-11275 DOI: 10.1021/jacs.3c01493

“Biological membranes host a wide range of lipid and protein components and can cluster them together or separate them from other components. Controlling the lateral distribution of molecules on the membranes of synthetic cells could help us reproduce some of the essential functionalities of living cells,” Lorenzo explained.

“So we challenged ourselves to build a device that could mimic this property, using DNA nanotechnology.”

DNA origamis to control the organization of membrane lipids  

For many years now, scientists have been using DNA and RNA, not for their genetic information, but as building materials for nanostructures. Members of the Di Michele lab, like Roger Rubio Sánchez, are specialized in DNA nanotechnology. Roger, first and co-lead author of the paper, used DNA origamis to build the DNA-origami line-actants (DOLAs).

“DOLAs are 2D analogs of soap molecules,” he said. “With them, we were able to program the 2D distribution of molecules on the membrane, by controlling the formation of phase-separated lipid domains that behave like 2D oil droplets in water.”

DOLAs were also used to control the three-dimensional shape of membranes, in particular, to induce the fission of small lipid vesicles.

Biomimetic fission pathway mediated by DOLAs. Source: DNA-Origami Line-Actants Control Domain Organization and Fission in Synthetic Membranes Roger Rubio-Sánchez, Bortolo Matteo Mognetti, Pietro Cicuta, and Lorenzo Di Michele Journal of the American Chemical Society 2023 145 (20), 11265-11275 DOI: 10.1021/jacs.3c01493

Potential developments

“Our DOLA concept could help better control synthetic cell division with possible applications in therapeutics. It could also help other researchers replicate signaling pathways that in living cells rely on the spatial distribution of certain molecules on the membrane or on the release of lipid vesicles,” emphasized Lorenzo.

“I hope our DOLAs spark interest in the synthetic cell community and that they take advantage of our concept, come up with new ideas with us,” added Roger.

Collaboration is essential to advance research on synthetic cells

Roger and Lorenzo, who work at the University of Cambridge, collaborated with Pietro Cicuta, also of the University of Cambridge, and with Bortolo Matteo Mognetti, of the ULB in Belgium.

“I have been working with Bortolo and Pietro for a very long time,” Lorenzo said. “Bortolo is a great soft matter theorist who helped us with the simulations and modeling. Pietro is an expert in the biophysics of lipid membranes. He shared his expertise with us and gave us access to his automated imaging suite. This allowed us to monitor the behavior of the synthetic membranes with great precision.”

Synthetic cell research is a multidisciplinary field that requires expertise in a wide range of areas such as biology, chemistry, physics, and mathematics. The path to building functional synthetic cells and the resulting technologies will require the effort of an entire community of researchers. It is therefore essential to support existing collaborations and encourage new ones.

More information:

DNA-Origami Line-Actants Control Domain Organization and Fission in Synthetic Membranes
Roger Rubio-Sánchez, Bortolo Matteo Mognetti, Pietro Cicuta, and Lorenzo Di Michele
Journal of the American Chemical Society 2023 145 (20), 11265-11275, DOI: 10.1021/jacs.3c01493

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