Reshaping the (micro)world on a (nano)raft

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This time we are looking at a study combining proteins, DNA origami and lipid particles! Sounds suspiciously like a cell… Let’s go!

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Reshaping the (micro)world on a (nano)raft

We are all familiar with cell membranes: they act as a barrier, keeping the inside of a cell separate from the world outside. But this is not their only function: cell membranes are incredibly dynamic, thanks to the interplay between lipids (the main components of membranes) and a huge variety of proteins that control molecular transport, signal transduction and even shape transformations in response to environmental changes! And yet, when it comes to our understanding of the workings of the cell membrane, there is still plenty of room for improvement (did you see what I did there?).

And to understand more, what better way than to build it? That’s exactly the philosophy behind today’s paper. The aim of the authors? To programmatically control membrane remodeling and molecular transport using fully synthetic materials: this can even open possibilities that don’t exist in nature! And what better way to achieve greater freedom with reduced complexity than DNA nanotech? Okay, I might be biased, but DNA nanotech is a great tool for interacting with lipid membranes and it’s a key player in building biomimetic modules for simplified synthetic cells. In particular, the DNA origami technique, where a single, long stranded scaffold is folded by short single stranded staples, has been particularly powerful to create nanoscale structures.

Okay, now let’s focus on the synthetic cell system they used. There are 3 main components:

• DNA origami nanorafts: these are square-shaped structures, which can change shape mediated by DNA strand-displacement, turning into an elongated rectangular shape, and they can also revert back to a square shape. These structures are functionalized with cholesterol, which inserts into lipid bilayers and ensure stable attachment to lipid membranes.

• Giant Unilamellar Vesicles (GUV): the authors used these large round vesicles, formed by a single bilayer of lipids, to mimic biological cell membranes.

• Protein pores: last but not least, natural membrane proteins, such as Ompf (a bacterial pore-forming protein), are introduced to transport small cargo across the GUV membrane

Now you can imagine these little DNA origami nanorafts floating on the surface of microscale lipid vesicles. And here is where the magic happens: the researchers add a specific DNA strands, causing the nanorafts to switch from square to rectangular. As a ton of nanorafts change shape, they creates a pressure on the membrane surface, which is also amplified by the increase order of the new conformation. This causes the GUV membrane to deform: this is a great example of nanoscale interactions driving microscale changes, a basic feature of biological systems! And the process is reversible: if you switch back the nanorafts to a square, the GUVs will go back to their original roundness. But this is not exactly what the authors had in mind. Instead, while the GUVs are under stress, they introduced protein pores, allowing small molecules like sucrose and ions to flow in. The molecular transport enabled by the proteins allows the GUVs to relax and return to their round shape, but it also has a different, unexpected effect. During this shape recovery, the interactions between the nanorafts and the membrane created new, large channels. To give you an idea, the proteins channels they used allow for cargoes up to 600 Da (a measure of molecular weight), while the artificial pores allowed passage of molecules up to 70 kDa, over 10000 times bigger! And these pores were also reversible: you just return the nanorafts to their square shape, and the pores close. Very elegant!

This was a beautiful approach to mimic biological matter, where shape is fundamental for function, by using synthetic systems. This study is interesting for both fundamental research and biomedical applications:

• Synthetic biology: The pores created by the DNA nanorafts are larger than common biological pores, and they could be a great way to easily shuttle large cargoes, like proteins or enzymes, across membranes.

• Drug delivery: The nanorafts could be programmed to create pores to deliver therapeutics contained in the GUVs to cells with high precision.

• Biosensing: The system could also be modified detect environmental signals and control molecular transport (and maybe remove pollutants from water!)

And these are just some of the possibilities! It’s interesting to see DNA nanostructures being combined with larger scale structures like GUVs, and I am excited to see what kind of functions can be created! If this is interesting, just go and read the paper here.

As usual, thank you very much for reading!

More room:

• Putting non DNA into DNA nanotech: If you think that DNA is too restrictive for you when building nanomaterials, rejoice: you are not alone. This study integrates non-DNA interactions into sequence-defined DNA polymers (SDPs), enabling the self-assembly of diverse nanostructures like SNAs, nanofibers, and nanosheets. These programmable materials support hybrid assemblies, nanoreactors, and advanced gene silencing therapies, expanding DNA nanotechnology for biomedicine and nanomaterials.

• Molecular origami in the spotlight: If you need some more variety for your nanoscale origami work, this review has got you covered. It explores molecular origami, expanding DNA origami principles to proteins and peptides for nanoscale design. Advances in protein and peptide origami enable precise folding control, with promising applications in electrochemical biosensors and nanotechnology. Very exciting stuff!

• Flipping RNA bases like it’s nothing: Are you feeling more like RNA today? No problem, just check out this study. It reveals that Nsp15, a coronavirus enzyme, preferentially cleaves uridines (U) that spontaneously flip out of RNA helices, aiding immune evasion. Using fluorinated RNA, NMR, mass spectrometry, and cryo-EM, researchers show that cleavage efficiency depends on U’s natural flipping tendency, suggesting Nsp15 targets accessible sites in viral RNA to regulate its levels. Very cool!

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