DNA Trash Cans: Outsmarting Tumor Signals with Origami Tech!

Designing DNA trash cans for tumor-signaling molecules? Crazy idea! But also, exactly what we cover today.

And the best part? It works!

DNA Tumor Traps

Cancer is a terrible disease, and a complicated one. Ask any cancer researcher: there are 100 types, each with its own characteristics.

What they all share is a talent for growing uncontrollably. Cancers remove the normal limits for cell growth, exploiting signaling molecules to create a permissive tumor microenvironment (TME).

In the TME, cancer cells, immune cells, extracellular matrix, blood vessels, fibroblasts, and signaling proteins interact to create a complex ecosystem. One high-impact player in this jungle is growth factor beta 1 (or TGF𝛽1 for friends).

TGF (yes, I will shorten it to just TGF from now on) is a cytokine often elevated in tumors. Many types of cells release TGF, and it has two (especially) bad effects:

• Helps the tumor become more aggressive, invading nearby tissues and metastasizing

• Suppress the immune response, facilitating evasion of the immune system and the progression of the tumor

So, a terrible double-whammy for the body.

And this has made TGF an important target for treatments.

But blocking TGF signaling is tricky. Small molecules and antibodies rely on a 1:1 ratio of blocking agents to TGF, with high doses and prolonged circulation. And this means side effects, such as liver toxicity!

DNA Origami NanoCaptors

This is where today’s paper comes in. The authors had a new idea to block TGF: capture it in the blood and get rid of it in the kidney. This approach needs the specific and efficient binding of a lot of TGF. And what better technique than DNA origami?

DNA origami allows the design of nanostructures starting from a single, long single-stranded piece of viral DNA. This is folded into shape by shorter single-stranded DNA pieces, creating DNA nanostructures with tens or hundreds of binding sites. And with low toxicity and immunogenicity, it’s perfect for biomedical applications!

DNA origami doesn’t have the best in vivo stability. It’s removed from circulation fast, accumulating in the liver and kidneys, where it’s destroyed. This is generally considered a problem: you don’t want your drug to be degraded in 10 minutes!

But this time is different.

The authors turned this bug into a feature: the DNA nanostructures capture tens or hundreds of molecules of TGF, and they are swiftly transported to the kidney and eliminated. Super smart idea!

The Designs: Barrel, Soccer Ball, and Icosahedron

So, how did they do it?

They built three 3D DNA origami shapes, all based on the same single-stranded scaffold. The molecular weight is practically the same, but the geometry and capturing capacity are different:

• DNA Barrel Captor (DBC): A barrel design, with the largest opening, and up to 150 internal binding sites (!). These sites are hidden in the structure, increasing the spatial confinement after binding to TGF.

• DNA Soccer Captor (DSC): This soccer ball is the largest and most flexible design. It has many windows of different shapes (hexagons, pentagons) and up to 90 internal handles.

• DNA Icosahedral Captor (DIC): The smallest design, a rigid icosahedron with 20 triangular, small windows and 30 internal handles.

But how do they capture TGF? Well, good question.

The authors loaded the handles with anti-TGFβ1 DNA aptamers, modified to increase resistance to nucleases in the blood. Cool!

Capturing TGF: In Vitro Tests

First, the authors confirmed that the aptamer binds TGF specifically. Then, they loaded the three designs with 30 aptamers to test the loading and capture:

• DBC30 was the best, binding 90% of the free aptamer in 5 minutes! And it also removed TGF in under 15 minutes. This is probably due to DBS30 having the biggest opening of the three and the most internally hidden aptamer sites.

• DSC30 had the slowest capture, with only 83% of aptamers captured after 5 minutes.

• DIC30 was in the middle, with between 85 and 90% of captured aptamer, slightly faster than DSC, even with smaller windows. Maybe an effect of the higher compactness?

The authors also noticed that structures with too many aptamers aggregated and collapsed because of interactions between TGFs. So there is a tradeoff: more binding increases capacity but raises aggregation risks. Which would be pretty bad if used in vivo (wild guess on my side)!

Testing in Cells: Does it Work?

Okay, it can bind TGF, but does it have an actual effect?

They tested the DNA captors in three different cellular systems:

• Tumor cells (A375, melanoma cell line): Adding TGF raises pSMAD2/3, so they used it to evaluate the effects of the DNA captors. Treating with DBC reduced pSMAD2/3 to 63% of the control! So, it worked.

• PBMCs: To test the impact of removing TGF on immune cells. Adding TGF increased differentiation into immunosuppressive regulatory T cells. Treating with DBC restored normal amounts of regulatory T cells and increased the population of effector T cells, which can help kill cancer.

• Cytotoxicity assays: The authors mixed PBMCs and A375 cells, and they showed that removing TGF increases the killing of tumor cells by immune cells!

So, using DNA captors to remove TGF blocks signaling pathways, shifts the immune cell subsets, and restores cytotoxicity. This confirms that their idea works! At least in cells.

Capturing TGF in Mice

The final test! Will it work in real organisms?

The structures resisted for a few hours in serum at 37°C, which is enough, since the half-life in circulation is around 10 minutes. So, they moved to testing the anti-tumor efficacy in mouse tumor models.

And it worked!

After injection, DBC cut circulating TGF to 50% within 4 hours, with levels rebounding after 8 hours. So, they tested redosing every 48 hours (6 times in total). In tumor-bearing mice, repeated DBC dosing reduced the tumor volume and increased the survival rate. And it worked even better when combined with anti-PD-L1 therapy! Immune profiling showed more tumor-killing T cells and reduced immunosuppressive regulatory T cells.

Tissue analysis showed increased concentrations of TGF in the kidneys, which indicates that the DNA nanostructures successfully captured and removed TGF! Plus, they didn’t see any damage or abnormality in the kidneys.

Turning Bugs into Features, DNA Origami Edition

Super cool work! It was a treat to read.

Many people (me included) see the fast clearance of DNA nanostructures as a problem, and it’s super cool to see someone challenging that assumption. And it uses another core feature of DNA origami: the capacity to bind lots of ligands, reducing the concentrations needed.

Now, there are still limitations:

• The short circulation time requires multiple dosing, even if it works well.

• The structures aggregate when too much TGF is bound, and this could be a problem for in vivo use.

• The aptamer affinity could be better (a common problem with aptamers)

But I love this idea. And it could be applied to other cytokines, or to other molecules! Although they have to be low in concentration, to avoid excessive doses (and costs).

So, cool work! Go and read it here.

If you made it this far, thank you! What do you think of DNA origami in therapies? Do you see some big roadblocks? Reply and let me know!

More Room:

• Guiding Proteins to Death: Very dramatic. But this paper is cool. It introduces a programmable DNA nanostructure that enables precise, reversible control of membrane protein activity using aptamers. By strategically positioning an aptamer inside a DNA tetrahedron, its binding to target proteins can be blocked; adding specific fuel or anti-fuel strands repositions the aptamer outside, restoring its ability to bind and trigger targeted membrane protein degradation. This allosteric regulation demonstrates a novel strategy for dynamically modulating molecular functions and controlling protein activity with high precision.

• Cryo-Em + ML = Love. Cryo-EM has pushed structural biology to new highs, but it’s still a very manual process. Now, a bit less. This study introduces E3-CryoFold, a deep learning framework that enables end-to-end training and one-shot inference for determining atomic structures from cryo-EM density maps. E3-CryoFold integrates 3D and sequence transformers with cross-attention and an SE(3) graph neural network to accurately reconstruct structures. Pretrained on simulated density maps, it achieves a 400% improvement in template modeling scores compared to Cryo2Struct, outperforms ModelAngelo, and reduces inference time by up to 1,000×, offering a faster, more accurate, and efficient solution for cryo-EM structure determination. Wow!

• Clicking Biology Into Place: Click chemistry won a Nobel Prize a couple of years ago, and for good reasons. These simple reactions made chemistry much more accessible! But what about biology? This perspective introduces click biology, an extension of click chemistry applied to living systems. It focuses on rapid, selective, and covalent reactions using natural cellular building blocks under cell-friendly conditions. Examples include split intein reconstitution, SpyTag/SpyCatcher isopeptide bonds, and suicide enzyme systems like HaloTag and SNAP-tag. Click biology enables powerful applications in molecular imaging, mechanobiology, vaccine development, and engineering cellular functions, offering new tools for precise and efficient biological research.

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