To understand why this advance matters, it helps to consider the broader challenge it addresses. Modern molecular diagnostics rely heavily on the ability to identify specific DNA sequences in complex biological samples, but traditional approaches often require laboratory infrastructure, enzymatic amplification steps, or elaborate sample preparation. Biosensors built from nucleic acids promise a simpler route: DNA and RNA molecules can be designed to change shape or activity when they bind a matching target, converting molecular recognition directly into a measurable output. The difficulty has always been specificity. Many disease-relevant mutations, such as point mutations in cancer genomes or single-nucleotide polymorphisms in pathogen genomes, differ from their benign counterparts by only one base pair, and conventional hybridization probes frequently fail to discriminate reliably between such near-identical sequences.

Base gap switches tackle this problem through their underlying architectural design. The concept centres on the deliberate introduction of a gap, or missing base, within a DNA duplex structure. In nucleic acid nanotechnology, strands are routinely programmed to hybridize through complementary base pairing, and small design choices, such as the placement of a mismatch, a bulge or an unpaired position, can dramatically alter the thermodynamics of binding. A gap at a precisely chosen position creates a local region of instability that renders the switch highly sensitive to what occupies that site. When the correct target nucleotide is present, the duplex is stabilized and the switch adopts its active conformation; when a mismatched base is present, the energetic penalty destabilizes the complex and the switch remains inactive. This mechanism allows the identity of a single base within a longer target sequence to be transduced into a large, switch-like change in behaviour.

The study characterizes these switches as transcriptional regulators, meaning that the conformational change driven by target binding modulates gene expression rather than simply generating a fluorescent or colorimetric signal. Transcriptional regulation by nucleic acid devices has been a long-sought goal in synthetic biology because it allows sensing and response to be wired directly into cellular or cell-free gene circuits. A DNA input that flips a base gap switch can, in principle, control the production of a reporter protein, an enzyme, or a therapeutic payload. By coupling molecular recognition at the DNA level to transcriptional output, the platform unifies sensing and actuation within a single programmable module, avoiding the need for intermediate signal-transduction layers that can add noise and complexity to engineered gene circuits.

The application of this principle to biosensing is where the technology shows its most immediate practical promise. According to the published findings, base gap switches enable single-nucleotide discrimination combined with sensitive detection, a combination that is essential for two of the most demanding areas of molecular diagnostics. The first is pathogen detection. Infectious agents often evolve rapidly, and closely related strains can differ in only a handful of genomic positions, yet those differences may determine transmissibility, virulence or drug resistance. A biosensor that reliably distinguishes single-nucleotide variants can therefore help identify not merely whether a pathogen is present, but which variant of that pathogen is circulating, information that is directly relevant to treatment decisions and public health surveillance.

The second major application area is oncology. Tumours accumulate mutations throughout their development, and many clinically significant cancer-associated variants are single-base substitutions. Liquid biopsy approaches, which aim to detect tumour-derived DNA fragments circulating in blood or other body fluids, depend on assays capable of finding extremely rare mutant sequences against a vast background of normal DNA. The reported ability of base gap switches to discriminate single-nucleotide differences while remaining sensitive enough to detect low-abundance targets suggests a role for this platform in the emerging landscape of non-invasive cancer diagnostics. Detecting cancer-associated DNA variants quickly, selectively and without heavy reliance on amplification infrastructure remains one of the central goals of molecular oncology, and nucleic-acid-based switches of this kind represent a promising engineering route toward that goal.

The programmability of the platform is a recurring theme in the study. Because the switch architecture is defined by base pairing rules rather than by any protein-specific recognition mechanism, the same design logic can, in principle, be reprogrammed to target arbitrary DNA sequences simply by changing the sequence of the constituent strands. This modularity distinguishes nucleic acid devices from antibody-based or protein-based biosensors, whose development typically requires new binding molecules for each new target. With base gap switches, retargeting the sensor to a new mutation is largely a matter of computational sequence design, which reduces development time and cost and makes the platform adaptable to newly emerging threats, such as novel pathogen variants or newly characterized cancer mutations.

The dual functionality of the switches also invites comparisons with other programmable nucleic acid technologies that have transformed the field over the past decade. Toehold-mediated strand displacement reactions, for example, have become a workhorse of DNA nanotechnology, allowing one DNA strand to invade a duplex and displace another through a short single-stranded region called a toehold. Toehold switches have been used to build synthetic gene circuits that respond to RNA inputs, and CRISPR-based diagnostics have exploited the programmable recognition of guide RNAs to detect viral genomes with high sensitivity. Base gap switches add to this toolkit by offering a mechanism in which the discriminating power is focused directly on the identity of a single base within the binding interface, a design principle that complements rather than replaces existing approaches and may be combined with them in integrated diagnostic workflows.

The broader significance of the work lies in its demonstration that DNA itself can serve as both sensor and controller within gene circuits. DNA-responsive biosensing is particularly attractive because many diagnostic targets, from pathogen genomes to circulating tumour DNA, are nucleic acids to begin with. A platform in which the target molecule directly gates transcriptional output shortens the path from sample to answer and supports the design of compact, programmable diagnostic devices. Such devices could eventually operate in cell-free expression systems, which require no living cells and can be lyophilized for field deployment, or in engineered living systems where a genetic circuit responds to DNA markers it encounters in its environment. The study’s demonstration of single-nucleotide discrimination and sensitive detection of both pathogen and cancer-associated variants indicates that the platform is relevant across these application spaces.

As with any emerging technology, translating base gap switches from the laboratory to routine clinical and environmental use will require addressing questions of robustness, sample compatibility, manufacturing consistency and regulatory validation. Real biological samples contain proteins, nucleases and vast excesses of off-target nucleic acids that can interfere with hybridization-based devices, and achieving the reported sensitivity and specificity under such demanding conditions is the definitive test of any biosensing platform. Nevertheless, the conceptual contribution is clear: by engineering a deliberate gap into a DNA duplex, researchers can create a switch whose activity hinges on the identity of a single nucleotide, and by wiring that switch into transcriptional circuits, they can turn molecular recognition into programmable biological function. The Nature Sensors study presents base gap switches as a step toward gene circuits and biosensors that are at once highly specific, readily reprogrammable and directly responsive to the DNA sequences that matter most in medicine and public health.

Subject of Research: Base gap switches as programmable DNA-based transcriptional regulators and biosensors for single-nucleotide discrimination of pathogen and cancer-associated DNA variants

Article Title: Base gap switches as transcriptional regulators and their applications as biosensors

Article References: Partington, Y., Dalla Via, B., Abgottspon, F., de Geyer, I., Cools, P., deMello, A. J., & Richards, D. A. (2026). Base gap switches as transcriptional regulators and their applications as biosensors. Nature Sensors. https://doi.org/10.1038/s44460-026-00134-z

Image Credits: AI Generated

DOI: 10.1038/s44460-026-00134-z

Keywords: base gap switches, DNA nanotechnology, biosensors, transcriptional regulation, gene circuits, single-nucleotide discrimination, pathogen detection, cancer-associated DNA variants, liquid biopsy, synthetic biology, nucleic acid switches, molecular diagnostics

For decades, scientists have largely relied on painstaking trial and error to coax proteins into crystalline forms. Crystallization enables scientists to determine the molecular structures of proteins, which can provide a blueprint for designing drugs, engineering enzymes and understanding disease.

Now, Northwestern University chemists have developed a new approach that replaces a tedious, unpredictable process with intentional design.

In a new study, Northwestern scientists repurposed flexible DNA strands as a blueprint and programmable molecular glue. Using DNA, the team directed proteins to assemble into diffraction-quality, intentionally designed crystal structures with atomic-level order. The strategy enabled the scientists to precisely control how proteins connect, creating unusually soft, flexible crystals while achieving the high structural order needed to determine protein structures.

Not only does the work simplify one of structural biology’s most difficult challenges, but it also overturns a long-held assumption that flexible building blocks cannot produce crystals with atomic-level order. The approach also could enable a new generation of flexible, customizable biomaterials for biosensing, drug delivery, bioelectronics and robotics.

The study will be published on Wednesday (July 29) in the journal Science Advances.

“The implications of this research are profound,” said Northwestern’s Chad A. Mirkin, who led the study. “Proteins are the building blocks of life, and their structure determines their function. When we intentionally determine those structures, we gain powerful new insights into how proteins recognize other molecules, catalyze chemical reactions and interact with living systems. That knowledge ultimately helps us identify new drug targets, design new medicines and engineer new materials.”

A nanotechnology pioneer, Mirkin is the George B. Rathmann Professor of Chemistry, a professor of medicine (hematology and oncology) and a professor of chemical and biological engineering, biomedical engineering and materials science and engineering at Northwestern, where he has appointments at the Weinberg College of Arts and Sciences, Northwestern University Feinberg School of Medicine and McCormick School of Engineering. He also is the founding director of the International Institute for Nanotechnology. Zhenyu Han, who was a graduate student in Mirkin’s laboratory at the time of the study, is the paper’s first author.

DNA as a blueprint and construction material

From fighting infections to digesting food, proteins carry out nearly every essential task inside living cells. To understand how these molecular machines work — and design drugs to target them — scientists need to determine their three-dimensional structures. 

X-ray crystallography is the gold standard for revealing these structures. In this technique, scientists first coax billions of identical proteins to assemble into a crystal. Then, they shine X-rays through the crystal and analyze the resulting diffraction patterns to reconstruct the protein’s atomic structure. But persuading proteins to form suitable crystals is often one of the most difficult and unpredictable steps in the process.

To improve this unreliable step, Mirkin turned to flexible snippets of single-stranded DNA. In a 1996 study published in Nature, Mirkin and his team used complementary DNA strands to assemble gold nanoparticles into ordered structures. Since then, his lab and many others have used DNA as a programmable bonding element to organize nanoparticles, polymers and other nanoscale building blocks into ordered structures.

“Over 30 years ago, the Mirkin group proposed the idea to take nanoparticles and modify them with DNA to create programmable atom equivalents,” Han said. “Nature’s nanoparticles are proteins. The difference between synthetic nanoparticles and proteins is that proteins are naturally uniform and molecularly precise. So, if we modify proteins with DNA and assemble them, we can form high-quality, atomically precise crystals, overcoming a decades-old challenge in the field of DNA-programmable assembly.”

How DNA pulls proteins together

Normally, proteins crystallize because parts of their surfaces happen to stick together through multiple, weak chemical interactions. By contrast, Mirkin’s team exploited DNA’s natural tendency to seek out its perfect match. Each DNA strand is made up of four chemical “letters” — A, T, C and G — that pair in predictable ways. For example, A always pairs with T, and C always pairs with G. When two complementary DNA strands encounter one another, they spontaneously snap together to form the familiar double helix.

In many ways, DNA bonds are more programmable than conventional chemical bonds. By changing DNA’s sequence, scientists can dictate which molecules connect and where they connect. That opens the door to building crystals with customizable architectures and mechanical properties for specific applications.

In the new study, Mirkin’s team attached short DNA strands to each protein. Then, DNA pulled neighboring proteins together, assembling them into precisely designed crystals. The team also varied key design features — such as DNA strand length and placement — to determine how each variable affected crystal formation. Finally, they used X-ray crystallography to examine the resulting crystals.

“The well-defined DNA-DNA interactions drove the assembly and crystallization process,” Han said. “As a result, the proteins not only adopted specific positions and orientations, but the atoms within each protein are also aligned in the exact same way throughout the crystal. When that happens, you can use single-crystal X-ray diffraction methods to determine their structure and see atomic-level details within the protein.”

Putting the method to the test

To further validate the approach, the team grew more than 1,000 protein crystals and determined the atomic structures of 28 distinct protein-DNA designs. Despite systematically changing DNA length and position, the resulting crystals consistently assembled into the designed architectures. That reproducibility, together with the direct visualization of DNA double helices linking neighboring proteins within the crystals, gave the researchers confidence that DNA — not chance — directed the assembly.

“These numbers show that we didn’t just get lucky,” Mirkin said. “We systematically demonstrated this approach across literally hundreds of possibilities and showed over and over again that it’s a reliable method. The DNA bond is a fundamentally new class of chemical bond, and this work shows how it can be used in ways that conventional chemical bonds cannot — to create a new type of material that yields new fundamental knowledge as well as technological breakthroughs that could significantly benefit society.”

The study, “Diffraction-quality, ultraflexible protein single crystals engineered with DNA,” was supported by the Air Force Office of Scientific Research (award number FA9550-22-1-0300) and the National Science Foundation (award number DMR-2428112).

Journal

Science Advances

Funder

Air Force Office of Scientific Research,
U.S. National Science Foundation

DOI

10.1126/sciadv.aeh2948

The significance of this research lies in its potential to mimic natural biomolecular condensates found within living cells. In biological systems, these condensates operate as dynamic compartments that organize cellular processes without the restraint of rigid membranes. Understanding how these natural structures function has fascinated scientists for years, and the new DNA condensates developed by the researchers provide an artificial analog that could perform similarly sophisticated roles in engineered biological systems.

Biomolecular condensates are key players in various cellular processes, influencing everything from gene expression to biochemical reactions. Their droplet morphology provides cells with the ability to compartmentalize biochemical reactions spontaneously, an advantage that artificial systems have yet to capture fully. This novel synthetic approach, however, opens the door to creating more complex artificial analogs that draw inspiration from nature’s intricacies. The unique properties of DNA nanostructures—with their programmable design and precision—position them as ideal building materials for advancing our understanding of synthetic cellular biology.

The research team, led by Professor Masahiro Takinoue, is probing uncharted territory in DNA assembly today. In their study published in JACS Au, they explore the anisotropic properties of their DNA nanostructures and the implications these have on how DNA condensates behave and interact. Unlike the many previous synthetic approaches that have employed uniform structures, the team’s string-like assemblies made from tetrahedral motifs introduce an anisotropic framework that enhances the self-organization of the resulting condensates.

One of the crucial elements of the study is how these unique tetrahedral DNA motifs maintain their structure when linked into chains. This rigidity prevents the environmental influences that typically degrade the stability of artificial constructs, leading to robust formations that can stretch and adapt under various physical stresses. For example, these novel condensates demonstrated unexpected mechanical resilience, being able to elongate into fibrous shapes without breaking under strain. Notably, this ability represents a considerable departure from conventional DNA assemblies, which typically succumb to rapid degradation or loss of structural integrity under such conditions.

In practical applications, the dynamic nature of these condensates is just as remarkable. The researchers successfully demonstrated that they could encounter physically confined spaces—akin to tiny blood vessels or cellular apertures—while maintaining their structural integrity and fluid-like behavior. This adaptability might hold significant potential for future drug delivery systems. As such, these DNA condensates may be capable of navigating the complexities of biological tissues, offering a significant leap in how therapeutic agents are transported within the body.

The research team further explored controlling these new DNA condensates using externally applied stimuli. By integrating photocleavable components, they unveiled the ability to disassemble the condensates in response to ultraviolet light. This disassembly process results in the release of individual DNA nanostructures that retain the capacity to penetrate cellular membranes effectively. Such methodologies could transform how drug delivery systems are formulated by including externally controllable elements that enhance precision and target specificity.

Furthermore, temperature responsiveness played a crucial role in this study as well, with the condensates exhibiting marked morphological changes as temperature varied. Such thermal dynamics could enhance their application in various bioengineering fields, allowing for real-time responses and adaptability. This study has invigorated the field with insight into how the structural and functional versatility of DNA nanostructures can bring forth innovative solutions to classic challenges faced in drug delivery and synthetic biology.

The research findings highlight a crucial shift in our approach toward creating artificial analogs of biological condensates. The anisotropic design of tetrahedral nanostructures reveals that compositional complexity is essential for achieving functionalities similar to those found in living systems. Consequently, this opens new avenues for biomaterial engineering where precise control over the physical attributes of the material can lead to enhanced performance in several applications.

Ultimately, this research underscores the significance of exploring the dimensional characteristics of building blocks in biomaterial design. By understanding and leveraging properties like anisotropy, researchers can construct DNA-based materials that replicate the sophisticated features observed in true biological systems. The future landscape of molecular devices, genetic engineering, and advanced drug delivery methods will undoubtedly be influenced by these pioneering advancements in DNA nanotechnology.

The growing intersection between synthetic biology and materials science offers promising possibilities for future research endeavors. With ongoing exploration and technical refinement, these newly developed DNA condensates could serve as a platform for creating novel biomaterials that are not only effective in therapeutic applications but perhaps also transformative in our understanding of cell-like structures in artificial environments.

As the team continues its work at the Institute of Science Tokyo, the implications of these findings will resonate across various scientific disciplines. The potential to engineer cellular functions artificially mirrors those seen in nature suggests a pivotal moment in biotechnology’s evolution, setting the stage for innovative methods of therapeutic interventions, tissue engineering, and synthetic biology.

Through a carefully structured approach that highlights the critical role of mechanical and structural properties in dynamic biological functionalities, the research stands as a landmark in our journey toward mastering the intersection of material sciences and biological engineering. This innovative work reinforces the imperative of understanding natural systems deeply as we endeavor to create their artificial counterparts and suggests that the future of biomolecular engineering is indeed bright.

In conclusion, the ongoing dialogue between natural processes and synthetic applications continues to evolve, paving the way for exploration into new domains and transformations in material sciences. Such pioneering research not only enhances our comprehension of DNA’s potential but also serves as a reminder of the remarkable adaptability and ingenuity of nature—a blueprint for future biotechnological innovations.

Subject of Research: DNA condensates and their properties through anisotropic nanostructures
Article Title: DNA Condensates via Entanglement of String-Like Structures Based on Anisotropic Nanotetrahedra
News Publication Date: 10-Jun-2025
Web References: https://doi.org/10.1021/jacsau.5c00421
References: Not applicable
Image Credits: Institute of Science Tokyo

Keywords

DNA, biomolecular condensates, nanostructures, drug delivery, artificial organelles, bioengineering, materials science

This development stands as a testament to the potential of DNA beyond its conventional role as a carrier of genetic information. DNA’s unique properties enable it to serve as a versatile material, offering a canvas for researchers to engineer elaborate nanoscale configurations. By strategically designing the base pairs that constitute DNA strands, scientists can create structures tailored to foster the precise placement of biomolecules, cells, and nanoparticles. These developments open avenues for groundbreaking applications in the realms of medicine, materials science, and advanced data storage.

Traditionally, the formation of DNA nanostructures necessitated rigorous temperature controls, with DNA strands subjected to heat followed by cooling, typically involving magnesium-ion-buffered solutions. Such requirements have constrained real-world applications due to the challenges associated with maintaining specific temperature settings. Moreover, the use of magnesium can lead to structural vulnerabilities in biological contexts, further complicating their potential use in therapeutic environments.

In a significant shift, the research team from UAlbany explored alternative methods that incorporate varied metal ions in different buffer solutions. The researchers demonstrated that DNA nanostructures could be successfully assembled isothermally at significantly lower, constant temperatures. These finding not only simplifies the synthesis process but also enhances the structural stability of the resulting nanostructures, thereby broadening their applicability in biomedicine and materials engineering.

Lead researcher Arun Richard Chandrasekaran explained the transformative nature of these findings, highlighting that their novel approach eliminates the reliance on sophisticated thermal cycling equipment. By assembling DNA nanostructures at moderate temperatures, the methodologies proposed by the team simplify the entire process of nanostructure synthesis, paving the way for practical applications in diverse fields. This new approach is particularly significant as it reduces thermal stress, protecting temperature-sensitive biomolecules that are often incorporated into artificial nanodevices.

The research illuminates pathways for using temperature-sensitive proteins—such as antibodies and enzymes—in conjunction with DNA nanostructures. By mitigating temperature-related risks during assembly, researchers can create refined DNA nanodevices potentially useful for drug delivery systems and diagnostic tools. This alignment of nanotechnology with biological applications highlights a promising future where tailored treatments might become possible.

Chandrasekaran’s enthusiasm underscores the transformative impact of the new findings, “This work brings us closer to imagining how these nanostructures could actually be made and used in the human body for applications like targeted drug delivery or precision diagnostics.” He emphasizes that while more research is needed before practical implementations can materialize, the ability to construct DNA nanostructures at physiological temperatures represents a significant milestone.

The collaborative research effort by the UAlbany team incorporated several different metallic ions in their studies, moving beyond traditional components to include nickel and strontium. These additions reveal the capacity for successful assembly at both ambient and body temperatures, diverging from previous reliance on magnesium ions. The immediate implication is a broader toolbox for scientists looking to craft DNA nanostructures that are easier to manipulate and deploy.

The exciting potential of this work extends beyond DNA nanostructures’ technical merits. The findings suggest that these new methodologies will not negatively impact cellular viability or immune responses, which indicates a welcome refinement for their applications in biomedicine. Further exploration in this field could lead to significant advancements in disease treatment and diagnostic methodologies, making previously complicated molecular interactions simpler and more reliable.

Chandrasekaran and his team propose to persist in this line of inquiry, aspiring to refine assembly techniques across various metal ions while rigorously assessing the biostability of the generated nanostructures. The goal is to create innovative nanotechnological solutions capable of addressing complex problems prevalent in medicine, health, and beyond.

The implications of these advancements resonate on numerous levels, suggesting novel methods that could expedite the design and production of biologically-compatible nanostructures. The collaboration extends beyond the UAlbany lab, attributing to the support from prestigious institutions including the National Institutes of Health and the U.S. Army Medical Research Acquisition Activity. This multidisciplinary approach also emphasizes the collaborative ethos essential in tackling challenging scientific questions that blend biology with nanotechnology.

The published research not only adds empirical weight to the foundation of DNA nanotechnology but also encourages dialogue around its future applications. As interdisciplinary teams continue to push the boundaries of biomedical research, the landscape of how DNA nanostructures can be cultivated and employed will undoubtedly evolve, promising a future rich with possibilities for innovation and discovery.

As the field stands at this essential crossroads, remaining cognizant of the implications and responsibilities tied to these advancements is crucial. The fusion of DNA technology with practical applications could redefine therapeutic protocols, while instilling the importance of ethical considerations in research and its applications. As DNA nanotechnology evolves, society must contemplate both the opportunities and challenges it presents, nurturing a balanced approach as the scientific community strives for transformative discoveries.

In conclusion, the pioneering work conducted by the UAlbany researchers opens thrilling new pathways for DNA nanostructure assembly, setting the stage for revolutionary applications across medicine and material science. By forging ahead in this promising line of research, they contribute significantly not only to our understanding of DNA but also to the membrane between technical achievement and biological utility, ultimately enhancing human health and potential.

Subject of Research:
Article Title: Counter ions influence the isothermal self-assembly of DNA nanostructures
News Publication Date: March 12, 2025
Web References:
References:
Image Credits: Arun Richard Chandrasekaran, University at Albany.

Keywords