Budding DNA Origami: Crafting Synthetic Cell Membrane Systems!

Can we turn DNA origami shells into synthetic cells? Well, today’s paper takes a strong step in that direction!

I needed some cool DNA origami after last week’s deep dive into quantum physics!

DNA-Built Vesicles

Membrane Budding: From Viruses to Organelles

Creating artificial cells is one of synthetic biologists’ biggest dreams.

These tiny, programmable factories promise to revolutionize drug delivery and sensing, thanks to incredible control over biological systems! But we are not there yet. One problem is that some natural mechanisms are very tricky to replicate.

Take membrane budding, where a portion of a cell membrane bulges out and pinches off to form a vesicle. It’s everywhere, from intracellular trafficking between organelles and endocytosis, to how viruses exit cells!

Proteins like clathrin guide this process. It’s a cool one: clathrin’s triskelion monomers assemble into a polyhedral lattice around vesicles, helping endocytosis. And they make for great EM images!

Controlling membranes and membrane budding at the nanoscale would be great! We could encapsulate specific molecules on demand and use them for programmed communication or targeted drug delivery!

DNA Origami: Protein-like Control, but Simpler

But sometimes proteins are a bit too complicated.

When replicating cells from the ground up, it’s better to start simple. And my favourite “shortcut” is DNA nanotech! And if you want to study self-assembly, DNA origami is your friend.

DNA origami can form almost any nanoscale shape using a long, single-stranded DNA “scaffold” kept together by shorter single-stranded DNA “staples”. The nanostructures are predictable, addressable at the nanoscale, and can assemble into complex structures! Perfect to create a membrane-interacting system.

DNA Origami and Membranes

And here today’s paper comes in.

The authors built a modular DNA-origami system that mimics clathrin-like membrane scaffolds and drives membrane budding, producing DNA-shell-coated vesicles (and more!).

By the way, this paper only has two authors, and the first one is an old PhD buddy of mine! Thanks, EU, for paying for our PhDs and making us meet.

Let’s look into the paper! It’s a cool one.

Nanostructures Designed for Budding

These are the ingredients for the DNA origami budding system:

• Triangular DNA origami subunits: These triangular DNA origami monomers assemble into icosahedral shells based on shape-complementarity, like LEGO!

• Membrane anchoring: Short cholesterol-modified DNA strands anchor the trianmediate the interaction between the triangles and the membranes. The authors can program the direction of the budding (inward or outward) by simply placing the cholesterol-oligos in the inner or the outer face of the triangle.

• Lipid membranes: Spherical lipid vesicles act as membrane models. They come in two sizes: giant vesicles (GVs), with a diameter up to 100 μm, and large vesicles (LVs), with a diameter of ~200 nm, perfect for cryoEM visualization.

• Triggering assembly: Add Mg ions: the membrane-bound triangles diffuse, assemble into cages and drag the membranes into buds.

And voilà! The authors creatively exploited the classic characterization toolbox of TEM, cryo-EM, fluorescence microscopy, and agarose gel electrophoresis to follow the kinetics of the process. They also studied variations of cholesterol placement/density and lipid compositions!

What Did They See?

So, did it work? Yes!

They observed membrane budding and the formation of vesicles, so they got creative.

They created 3 variants of the system:

1. DNA-shell-coated vesicles (DCVs): When cholesterol is placed in the inner face of the triangle, the DNA icosahedral shells encapsulate lipid vesicles (outward budding).

2. Vesicle-coated-DNA shells (VDCs): With cholesterol on the outside face of the DNA triangles, you will get inward budding, creating a vesicle surrounding the DNA origami structure! This forms an internal compartment, similar to an endosome! Pretty cool.

3. Vesicle-coated DCVs (VCDCVs): They created double-layered vesicles! They first produced DCVs, but this time they used triangles with additional ssDNA linker handles. Then, they mixed the DVCs with LVs with the complementary ssDNA, and voilà! Inner vesicle, DNA shell, outer vesicle. Like an organelle-in-organelle!

Mechanism: Why Does it Work?

The authors took a page from the engineering book and studied their own system extensively!

The coolest part is why this budding process works at all.

In a way, the process is similar to clathrin, its natural counterpart. The triangles form a scaffold for the membrane; their self-assembly deforms the membrane and finally forms the vesicles.

In cells, the energy for this process comes from ATP and various elements of the cytoskeleton. Here, it comes from the base stacking between the different DNA triangles. When the monomers assemble, the energy “accumulates” until it’s enough to curve the membrane! Very cool.

Interestingly, the neck scission (the last part of the budding) seems to be a delicate point of the process. The scission happens because the geometry of the shell forces it, and the energy accumulated from the assembly is high. And sometimes this process goes wrong, creating shells with a “scar” (a missing triangle). Poor shells!

Why This is Cool (And Some Precautions!)

Amazing work! And great figures.

This work could be applied in both basic research and in the “real world”:

• Model for membrane studies: This is a simplified version of natural vesicle budding and scission. It makes for a great platform to study membrane mechanics and energetics in a bottom-up engineered system!

• Nested compartments: They could be used for drug delivery or to build synthetic organelles. I’m thinking especially about the double-vesicled shells, which could better protect the payloads! Add to that the programmability of DNA origami: aptamers, proteins, or small molecules!

The authors highlight some limitations with their current system:

• High Mg concentration, far from physiological, which could limit the translatability of findings

• Rigid membranes are a problem for this assembly-based system: there is not enough energy to bend them (natural systems use motor proteins)!

But it’s a cool system! I can’t wait to see others using it. So, read all the details (and admire the cool figures!) here.

If you made it this far, thank you! What do you think of DNA origami? Have you worked with lipid vesicles? Reply and let me know!

More Room:

• AI + Enzymes: It’s hard to keep up with all the advances at the interace between AI and proteins. This perspective envisions how AI could revolutionize enzyme discovery, uncovering vast numbers of potential biocatalysts beyond what natural evolution produced. While only a small fraction of enzymes is known, AI can decode and design new sequences and structures, enabling catalysts for reactions unknown in nature. Building on directed evolution, AI may allow scientists to genetically encode nearly any chemistry, transforming biocatalysis for sustainable production, pollution cleanup, and medicine.

• Cheaper DNA Origami: DNA origami is cool, we have seen it time and time again. But it’s also not cheap. This study presents a simple, sustainable method to recycle DNA origami staple strands, using molecular weight cut-off ultrafiltration. The recycled staples can be reused in multiple folding cycles without compromising structural integrity or functionality, maintaining performance over at least five rounds. This approach reduces staple costs by up to 33%, with a theoretical maximum of 41%, offering an easy and cost-effective improvement for large-scale or highly modified DNA origami fabrication workflows.

• Optogenetic Meets Actin: We have just seen how powerful light is to activate biological systems. This study introduces OptoVCA, an optogenetic system that enables precise, light-controlled assembly of actin networks on lipid membranes via the Arp2/3 complex. By adjusting illumination parameters, researchers can tune actin network density, thickness, and shape. Using this platform, the team found that dense actin networks block myosin filament penetration, while ADF/cofilin can still access but disassemble them less efficiently. These results show that actin network density distinctly regulates the behavior of actin-binding proteins, offering new insights into how cytoskeletal organization controls cellular mechanics and dynamics.

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