DNA Origami Membranes: Molecular Mimicry Rewrites Cellular Architecture!

DNA, RNA, and proteins, all wrapped into a lipid membrane. Those are the basic ingredients of a cell. But what if we took a completely different approach and got the same results?

Today’s paper pushes us into a world where DNA copied the lipids’ homework, creating membrane-like megastructures!

DNA Mimics Lipids

SynBio: Bottom-Up vs Top-Down

Building artificial cells is synthetic biology’s boldest dream.

Scientists follow one of two routes:

• Top-down: Start with a cell and simplify or modify it (for example, making E. coli produce something of value).

• Bottom-up: Begin with non-living blocks and build structures and functions similar to cellular ones.

Me? I think that the bottom-up approach is just cooler (but I’m also no synthetic biologist, so it doesn’t really matter).

Artificial cells promise complete control over biological systems, and they could revolutionize sensing, drug delivery, and biomanufacturing. But slow your horses, we’re not there yet. Most natural mechanisms are tricky to replicate.

Cellular Compartments: Specialized Pockets

One of these tricky mechanisms is compartmentalization (and not only because I never spell it right).

Natural cells rely on different compartments to create local chemical environments. This separates functional units, enabling the hierarchical organization typical of living systems.

Now, biology generally relies on different systems:

• < ~ 100 nm: At this scale, proteins create organized, hollow containers; for example, virus capsids!

• > ~ 100 nm: Lipid bilayer membranes dominate here, and they are less ordered and more dynamic.

Synthetic biologists have replicated both, with their strengths and weaknesses:

• Proteins/DNA cage-like assemblies
  They can display molecular patterns, and the particles are uniform in size. But creating larger assemblies is complicated.

• Lipid membranes
  Much easier to form, but lacking the addressability of their protein or DNA counterparts.

You know that I have a soft spot for DNA origami.

DNA origami forms nanoscale shapes using a long, single-stranded DNA “scaffold” held together by shorter single-stranded DNA “staples”. These nanostructures are predictable, addressable at the nanoscale, and easy to program. But things get messy when assembling them into larger constructs!

Dipids: Nanoscale Precision with Lipids’ Dynamisms

Can we combine the nanoscale precision of proteins and DNA assemblies with the ease of use of lipids?

According to today’s paper, yes.

The team introduced Dipids, a whole new class of DNA origami building blocks. They mimic the flexible interactions of lipids and form membrane-like monolayers, closing into vesicles or rolling into tubes.

All while keeping the nanoscale precision of DNA origami!

Dipids’ Design Principles

A Dipid is a single DNA origami barrel.

Around 30 nm in diameter, Dipids are decorated with 30 weak, flexible single-stranded DNA “links” sticking out from the surface. These are the secrets to forming “membrane-like” assemblies!

Each DNA links contain 3 domains, each with a specific job:

• “Sticky” domain: palindromic sequences that let monomers weakly bind to each other.

• “Curvature” domain: a variable poly-T stretch allows control of the curvature, turning the monomers more into cones than barrels!

• “Flex” domain: a poly-T stretch allows the connections to relax if local strain accumulates (so the membranes don’t break).

By changing only these 3 domains, leaving the monomer body untouched, the team can program the size of the membrane-like assemblies!

To make the whole thing more user-friendly, they built a computer-aided pipeline. Using classical mechanics models, they predict the curvature → the membrane radius → the container size.

With this pipeline, they generated 74 monomer variants (!) and validated them using computer simulations and TEM.

From XS to XXL: Containers for Everyone

Now that we know all about the monomers, let’s see what the team assembled!

By tuning the mixing ratios and the cone angle (via the curvature domain), they assembled containers across 6 different sizes: XS, S, M, L, XL, and XXL, with diameters ranging from 119 nm all the way to a crazy 1.2 μm!

The smaller XS/S containers are round and approximately the same size as large protein assemblies, such as the HIV capsid. The larger ones? The XL is on the same scale as an E.coli cell, and the XXL one is even larger!

We’re talking about micrometers here.

And to turn an S monomer into an XXL one, you just have to change 24 binding strands, for a total of 160 dollars (today). Amazing versatility!

It feels like the researchers achieved ease of use comparable to lipids. Even the enormous XXL containers assemble in 24h, a fraction of the traditional multi-day annealing of other structures!

Cryo-ET and TEM reconstructions revealed closed hollow containers with a mix of hexagonal and pentagonal packing, a defect needed to close a curved sheet. Plus, the monomers are not limited to forming containers. With the right tweaks, they can also roll into tubes!

Just like lipid membranes, Dipid membranes are semipermeable, letting only particles below a certain size cross. In this case, the permeability assays with dextrans showed size-selective permeation consistent with 3 sizes of pores:

• 19 nm internal barrel pore

• ≈13–15 nm trimer pores, at the interface of 3 monomers in the hexagonal lattice

• 30 nm pores, when a pentagonal lattice deforms the local environment

Plug-and-Play DNA Membranes

DNA origami can create cool structures, but it’s amazing at functionalizing them.

Picture that, on the micrometer scale!

Thanks to their modular design, the team combined monomers with different functionalities, without disrupting assembly.

They provided 3 examples:

• In vitro transcription modules
  The team anchored a DNA template for the fluorescent dBroccoli aptamer inside the membrane. An externally added T7 polymerase diffuses in and transcribes the aptamer, which localizes to the membrane. Doesn’t it remind you of an organelle?

• Subcompartments
  They pre-assembled S containers and other DNA origami cages, and then assembled XXL containers around them, creating subcompartments. Awesome!

• Heterogenous pores
  The standard Dipid monomer has a 30 nm diameter, but they can also be made bigger. Co-assembling of 30 nm barrels with larger 60 nm ones creates functional containers with “rafts” of larger pores!

A New Challenger for Membrane Engineering?

Super cool work!

I first saw some EM pictures on LinkedIn, and I had to look twice to be sure I didn’t misread the scale bars. Insane how big the containers get!

And I loved the concept. We all know about lipid membranes, but creating them out of DNA origami? So unconventional.

The Dipid system has many advantages:

• Programmable size 100 nm → 1 μm

• Tunable curvature and porosity

• Modular functionalization

• Structural stability compared to lipids

So, I feel like they achieved their goal!

And the drawbacks are similar to lipid membranes:

• Polydisperse

• Sensitivity to ionic conditions and annealing protocols

• Deviation between designed and real diameters at large sizes

But as always with DNA origami, the real problem is the cost and complexity of producing them at scale. I’ve been seeing this more and more popping up. Time for a solution!

But go read all the details here! It’s an exciting read, and there is more than I could cover here.

If you made it this far, thank you! What do you think of these giant DNA origami containers? How do you think they compare to more standard techniques? Reply and let me know!

More Room:

• DNA Origami Flowers: What’s up with all the flower-themed DNA work lately? Not sure, but you won’t see me complaining. This paper presents a biomimetic “cloverleaf” DNA origami system that can reconfigure its shape, sense specific DNA sequences, and assemble into larger structures. A flexible version (Leaf4) can fold into a closed ring through strand exchange, while a stabilized version (Lucky4) functions as a sensor using split capture strands that bind and release target DNA. In the presence of a target, two Lucky4 units also join into a stacked assembly. This system showcases dynamic DNA origami with controllable shape and modular sensing capabilities.

• More Imaging, Better Imaging: I’m no microscopy expert, unfortunately. But I love looking at images! And for all the microscopy fiends out there, this paper presents a simplified, high-throughput method for multiplexed super-resolution imaging. By pairing fast DNA-PAINT docking strands with their mirror-image (left-handed DNA) counterparts, the authors achieve rapid, efficient 12-target imaging without relying on secondary labels. Tested on synthetic samples and cells, the approach enables 3D mapping of dense neuronal protein networks with ~15 nm resolution over large fields of view, offering a powerful tool for spatial proteomics.

• Mixing DNA Origami and Viruses: Did you feel like you wanted some more DNA origami? Great, me too. This paper describes a hybrid nanoreactor that combines the programmability of DNA origami with the protective, selective gating properties of virus capsid proteins. Enzymes are precisely positioned inside a DNA origami scaffold, and capsid proteins are assembled around it to control substrate access, enhance stability, and enable size-selective uptake. The capsid shell also shields the enzymes from degradation and can be functionalized for targeted delivery. This modular approach offers a versatile platform for studying capsid properties and for developing engineered biocatalytic or biomedical systems.

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