Besides its generic function, DNA is also an important structural material in nanotechnology. Using a process called DNA origami, researchers have been manipulating DNA strands and molding them into increasingly complex two- and three-dimensional shapes for decades. These nanostructures interact naturally with biological systems and show promise for applications ranging from medicine to agriculture. Yet, structural reliability has been a long-standing obstacle.
Now, an international group of researchers at Newcastle University has developed a simulation tool to increase the reliability of DNA origami assembly. Their findings, published in Nature Communications, show that the choice of DNA sequence itself is critical to successful folding, a factor often overlooked in the rush to design ever more complex structures.
DNA origami is a method in which a long single-stranded DNA “scaffold” is mixed with multiple shorter pieces called “staple” strands. These staples bind weakly to their complementary sites along the scaffold at elevated temperatures, and as they cool, they force the entire structure into a known geometry. However, unwanted interactions between strands could disrupt such assembly, leading to misfolded structures that reduce fabrication yields.
It can predict and prevent such off-target interactions, allowing researchers to choose scaffold sequences with a higher likelihood of folding correctly. This approach was validated experimentally, and it showed that sequences predicted to have fewer off-target interactions would fold well (2D), and structures predicted to give numerous nonspecific offsets often failed even with accurate geometric fit (3D)
Study lead author Professor Natalio Krasnogor, Newcastle University, explained:
“The new paper uses a multi-objective computational framework that optimizes DNA origami assembly by selecting scaffold sequences that minimize off-target interactions, which are known to cause kinetic traps and reduce folding yield. This is crucial for researchers aiming to improve the fabrication yield and mechanical uniformity of custom-designed DNA origami objects for downstream biomedical or agritech applications.”
From Bordeaux, Dr Juan Elezgaray added:
“DNA origami is used nowadays as an almost routine tool to create nanostructures. We have shown that the method’s success can be seen, in part, as a matter of chance, largely linked to the choice of a readily available scaffold. Other choices would have led to a far less efficient method.”
Professor Emanuela Torelli, Università degli Studi di Udine and Visiting Researcher at Newcastle, emphasized the practical potential:
“We provide a novel software able to select optimal DNA sequences for a given target origami nanostructure shape. Looking forward, our in-silico design tool can refine the packaging via origami folding of a specific cargo (e.g., mRNA) and the synthesis of nano-vehicles for exogenous biomolecules delivery to cells.”
Professor Ariel Kaplan, Israel Institute of Technology, highlighted the broader implications:
“DNA origami is often described as programmable self-assembly, but this work shows that the DNA sequence itself matters more than is usually assumed. By combining computational design, imaging, and single-molecule optical tweezers, we found that avoiding unintended interactions improves not only folding yield but also the mechanical uniformity of the resulting nanostructures. That reliability is essential for moving DNA origami toward future biomedical, biotechnological, and materials applications.”
And from Bonn, Professor Michael Famulok noted:
“We have begun to successfully incorporate the Sequence Selector algorithm in our research to systematically optimize origami staple sets and thereby obtain more robust origami designs. This method complements existing origami design tools that we have used so far and helps reduce misfoldings caused by kinetic traps or nonspecific interactions.”
This is more than just a technical efficiency play. Enhancing DNA origami reliability enables the more realistic pursuit of functional applications, from molecular-level agricultural tools to nanoscale drug delivery systems and targeted biosensors. The software allows these structures to be designed much more systematically, reducing the element of luck that has previously hampered the technique.
In conclusion, DNA origami is shifting from an empirical folding method to an accurate branch of structural science. Integrating the computational framework will likely enable the creation of functional DNA-based nanomachines for medicine, biotechnology, and related areas.
