In this interview, AZoNano speaks with Dr. Kun Zhou, an Associate Research Scientist at Yale University, about recent advances in DNA nanotechnology. He discusses his work on a DNA-based nanodevice that applies defined forces to proteins, as well as collaborative efforts to expand the DNA alphabet to create more programmable nanostructures. These innovations could broaden the capabilities of DNA-based materials and tools.
Could you tell us a bit about yourself, your lab, and the kinds of questions your group is trying to answer?
I earned my PhD in cell biology from the Chinese Academy of Sciences, and I am now an Associate Research Scientist in Chenxiang Lin’s lab at Yale University. My research focuses on DNA nanotechnology, programmable protein–DNA hybrid assemblies, and mechanobiology.
I am particularly interested in using DNA as a programmable material to develop tools that enable us to investigate biological mysteries that are otherwise difficult to address.
Our lab has developed DNA origami devices with precise geometry and function control to study biological molecular systems. A big theme in our work is that DNA is as much an engineering material as a genetic material.
Could you explain the core idea of your DNA nanodevice paper in simple terms? What does the device do, and why is that useful?
We built a tiny DNA-based device that can grab a protein and pull on it. This allows us to study what happens when force changes a protein’s shape, and whether that changes what it binds to.
We used talin as a model system. Talin is a key mechanosensitive protein that helps cells connect to their surroundings, and it changes shape when it experiences force. Using our device, we showed that force stretches talin and promotes its binding to vinculin. We also found evidence for a previously unrecognized force-dependent binding partner of talin.
Existing force methods are excellent for single molecules, but they are not well-suited for bulk biochemical assays or many structural biology workflows, so our device begins to bridge mechanics, ensemble biochemistry, and structural analysis.
More broadly, why are you so interested in how mechanical force changes protein shape and protein binding? What makes that such an important biological question?
Mechanical force plays a key role in how cells sense and respond to their environment. Physical cues such as tension, compression, and tissue stiffness can change protein structure, expose hidden binding sites, and alter how proteins interact with their partners.
These force-sensitive molecular events are important in many biological processes, including cell adhesion, migration, and immune responses. In other words, mechanical force is not just a physical signal. It can be converted into biochemical signals that regulate cell behavior.
By developing tools that apply defined forces to proteins, we can begin to understand how mechanical inputs are converted into molecular and biochemical responses. This helps us connect protein structure, molecular interactions, and cellular function in a more direct way.
Professor Martin Schwartz said that “we haven’t been able to establish a deep molecular understanding of how force acts on proteins, because there has been no way to do structural biology on proteins under tension.” What has been missing technically, and how does this nanodevice begin to close that gap?
The main missing piece has been a way to study proteins under force with tools that also work for bulk biochemistry and structural analysis.
Existing methods such as optical or magnetic tweezers are powerful, but they are often single-molecule methods. Fluorescence microscopy enables the detection of protein-protein interactions, but it is hard to connect this to more conventional biochemical workflows and structural analyses.
Our device starts to bridge that gap. It applies force in a programmable way using DNA nanotechnology, but it also works in formats compatible with electron microscopy and proteomic analysis.
In the talin experiments, what do you see as the most important biological finding? Is it mainly that you can watch force extend the protein, or that you can connect that extension to new binding interactions?
For me, the key point is that force-dependent extension is directly linked to force-dependent binding. It is not just that talin gets longer. Rather, what it can interact with changes.
That is especially clear from the vinculin results, where force helps expose binding sites on talin. The filamin results also suggest that there may be other force-regulated talin interactions that we did not fully understand before.
More broadly, the findings show that mechanical force can control protein behavior by changing which binding sites are exposed and which molecular partners can interact with the protein. This provides a direct link between force, protein structure, and cellular signaling.
You mention that the device is modular and could be adapted to a broad range of proteins. Which other proteins or systems are you most excited to study next, and why?
I’m especially excited about other mechanosensitive proteins involved in cell adhesion and force sensing, such as integrins, cadherins, and PECAM. These proteins are central to how cells sense their physical environment and convert mechanical cues into biochemical signals.
More generally, I’m interested in systems where force does more than simply deform a protein. Force can change which binding sites are exposed, which partners are recruited, and how signals are passed through the cell. These are the kinds of problems where programmable DNA-based force tools could be very useful.
Prof. Schwartz also suggested that the next step could be to determine protein structures with and without applied force, which could eventually help identify drugs that alter how proteins respond to force. Could you unpack that a bit? What does it really mean to alter how cells sense force, and what kinds of doors could that open in medicine or biology?
It means asking whether we can change how cells respond to mechanical signals. Cells do not only respond to chemical molecules. They also read physical information from their environment, such as tissue stiffness, stretching, or shear stress.
Mechanosensitive proteins help cells read that information. If force makes a protein easier or harder to open, or changes which partners it can bind, the cell may behave differently.
In the long term, that could open up a new therapeutic idea: not only targeting chemistry, but targeting mechanical responsiveness.
In the Science Advances paper, you ask whether DNA nanoscience could be better supported by “intelligently designed” DNA base pairs with greater stability and programmability. Am I right in thinking those “intelligently designed” base pairs are the AEGIS bases, including the “fat” and “skinny” helices you describe in the paper? And if so, what do those extra base pairs let you do that standard DNA does not?
Yes. In that paper, we explored the assembly of new DNA nanostructures using AEGIS bases developed by Professor Benner. These artificial base pairs expand the DNA alphabet beyond the natural A, T, G, and C bases.
The key idea is that extra base pairs give us more than just more sequence choices. They can also change the physical properties of DNA structures. For example, they can support duplexes with different geometries, including the “fat” and “skinny” duplexes described in the paper.
For DNA nanotechnology, this gives us a larger design space. It may allow us to build nanostructures with greater programmability, different shapes, and improved stability compared with structures made from standard DNA alone.
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You write that the structures in this work are built from nucleobases that “escape those limitations” imposed by standard DNA chemistry. Why is escaping those limitations so powerful? What becomes possible once you are no longer restricted to the natural four-letter DNA alphabet?
The natural DNA alphabet is extremely powerful, but it gives us only four letters to work with. By adding new base pairs, we increase the number of sequences and interactions that can be programmed into a DNA nanostructure.
In this work, the expanded alphabet also gave us practical advantages, including improved thermal stability and nuclease resistance. That matters because DNA nanostructures often need to remain intact under challenging conditions.
More broadly, moving beyond the four-letter alphabet allows us to design DNA-based materials with a wider range of properties. We are changing the sequence code and what kinds of structures and assembly behaviors DNA can support.
Could you explain the difference between the “fat” and “skinny” duplexes in intuitive terms? What physically changes, and why does that matter for the kinds of nanostructures you can build?
The simplest way to think about them is that they are DNA-like helices with different physical dimensions. Fat duplexes form from larger pairing units, while skinny duplexes form from smaller ones. As a result, the helices have different geometries.
That matters because nanoscale geometry affects how DNA building blocks pack together. Small changes in helix size or shape can lead to very different assembly outcomes. In our study, fat systems tended to form nanotubes, while skinny systems formed more open two-dimensional lattices.
One of the striking ideas in that paper is that expanding the DNA alphabet gives you not just more sequence diversity, but a new structural dimension. What do you think is the most exciting consequence of that for the future of DNA nanotechnology?
To me, the most exciting consequence is that the DNA alphabet itself becomes a design parameter. Traditionally, DNA nanotechnology has relied mainly on the programmability of base pairing. With expanded alphabets, we can also tune the physical behavior of the building blocks.
This could help us build DNA nanostructures that are more stable, assemble more cleanly, and access shapes or functions that are difficult to achieve with standard DNA alone. It moves the field closer to designing DNA as an information-carrying molecule and a versatile material for nanoscale engineering.
These two papers seem very different on the surface: one is about force-sensitive proteins, the other about expanding the DNA alphabet. Do you see them as part of the same bigger research direction?
Yes, definitely. On the surface, the two papers look quite different, but both are about using DNA as a programmable engineering material.
In one case, we use DNA to build a tool for studying force-sensitive proteins. In the other, we redesign the DNA material itself by expanding the genetic alphabet. Together, they show two sides of the same idea: DNA can be programmed to store information and build new tools and materials for biology and nanotechnology.
Were there any results in either paper that surprised you?
In the nanodevice paper, I was surprised by how directly force-induced talin extension could be linked to changes in binding behavior. It was not just that talin became longer under force; the force changed how talin interacted with its partners.
Although talin is a well-studied mechanosensitive protein, our device allowed us to observe force-dependent binding behavior that had not been fully appreciated before.
In the Science Advances paper, it was surprising to see how clearly different duplex geometries led to different assembly outcomes. The fat and skinny systems formed distinct structures, including nanotubes, open two-dimensional lattices, and hybrid structures that could self-segregate.
Both papers came out very recently. Since then, what has your group been working on, and what are the next experiments you’re most excited about?
The next steps are about pushing both directions further. For the force nanodevice work, we are interested in improving structural resolution and developing better ways to read out force while observing protein behavior.
For the expanded-alphabet work, the project was initiated at Emory University in collaboration with Professor Yonggang Ke and Professor Steven Benner at the Foundation for Applied Molecular Evolution. Looking ahead, we are interested in exploring more synthetic base-pair systems and using them to build functional biomolecular machines.
Looking ahead a few years, what would success look like for this line of research? What would you hope people in the field could do that they cannot do now?
On the mechanobiology side, success would mean that studying proteins under force becomes much more routine, enabling researchers to directly connect force, structure, and binding across many systems.
On the DNA materials side, success would mean that expanded-alphabet systems become practical tools for building DNA nanostructures that are more stable, more programmable, and more capable than structures made with standard DNA alone.
I hope these efforts help expand DNA nanotechnology toward tools and materials that are precisely designed, responsive, and useful for studying biological systems in ways that are difficult today.
About Kun Zhou
Dr. Kun Zhou is an Associate Research Scientist in Chenxiang Lin’s lab at Yale University. His research focuses on DNA nanotechnology, DNA-origami-based molecular tools, and protein–DNA assemblies. He develops nanoscale systems to study protein structure, molecular interactions, and force-regulated biological processes.
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