RNA Nanotechnology: How RNA Is Transforming Biology and Advancing Nanotool Design

For many years, RNA was considered the overlooked ‘middle child’ of biology. DNA was widely regarded as the blueprint of life, proteins were seen as the cell’s molecular workforce, and RNA was treated mainly as a messenger that carried genetic instructions from DNA to the machinery responsible for producing proteins.

Research, particularly since the 1990s, has transformed that picture. Scientists have discovered that RNA can perform a wide range of active and unexpected functions. “It’s kind of like a dark horse of biology, it does so many things,” says Elisa Franco, a bioengineer at the University of California, Los Angeles.

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Biologists have identified RNA molecules with catalytic properties similar to those of enzymes, as well as RNA structures that bind strongly to specific target molecules. These capabilities are important for developing precise and effective medicines. Researchers can also fold RNA into complex three-dimensional shapes, allowing it to act as a scaffold for molecular interactions and biological processes. This flexibility has accelerated interest in RNA nanotechnology, says Franco. “There’s a lot of RNA that nobody knows what it actually does.”

RNA’s versatility is supported by its simple genetic code, which consists of only four nucleotides: adenine (A), uracil (U), cytosine (C) and guanine (G). These building blocks allow RNA to carry genetic information while also forming structures and performing functions usually associated with proteins. That combination makes RNA attractive to researchers who want to control the behaviour of living cells for medical and biotechnology applications, says Fei Zhang, a chemist at Rutgers University at Newark in New Jersey.

Advances in nanotechnology are now helping scientists turn these properties into a new generation of RNA-based molecular tools. The applications range from compact genetic switches that adjust cell activity to sophisticated RNA nanostructures that could act as miniature production platforms for medicines and other valuable materials.

However, major gaps remain in scientists’ understanding of how RNA folds, moves and functions inside living cells. Resolving these challenges will be essential if RNA nanodevice designs are to be translated reliably from the laboratory into practical technologies.

RNA riboswitches: an unexpected genetic control system

RNA’s versatility begins with its behaviour at the molecular level. To produce a protein, a cell first copies DNA into messenger RNA (mRNA). The mRNA carries genetic instructions to the cell’s protein-making machinery. Although mRNA is often represented as a simple linear sequence, its nucleotides can pair with one another — A with U and C with G, for example. These interactions cause the RNA strand to fold back on itself, creating secondary structures such as loops and stems.

These folded regions can provide binding sites for proteins and influence how the cell interprets the mRNA sequence. In some cases, RNA structures perform more complex functions. One example is a riboswitch: an mRNA-based molecular control system that binds to a specific target and then switches protein production on or off. Researchers are investigating how engineered riboswitches could become compact genetic-control modules for regulating individual genes.

One challenge is that most natural riboswitches respond to metabolites — small molecules produced or consumed during ordinary cellular reactions. Because metabolite levels can be difficult to control, researchers are screening large libraries of RNA sequences to discover switches that respond predictably to existing medicines with established safety profiles.

In 2025, a team led by Jörg Hartig, a chemist at the University of Konstanz in Germany, reported an engineered riboswitch that increased expression of a target gene in mammalian cells by up to 100-fold when exposed to allopurinol, an approved treatment for gout¹. Hartig says that newer riboswitches developed by his laboratory can increase gene expression by as much as 1,000-fold.

In the future, such RNA switches could be incorporated into gene therapies and delivered to cells using established technologies, including viral vectors and lipid nanoparticles. Once inside the body, a patient could use an existing medicine to adjust therapeutic gene activity in real time — effectively turning gene expression up or down like a dimmer switch.

For example, a gene therapy could restore production of a metabolite that is missing in a patient with a metabolic disorder. Keeping that therapeutic gene active continuously, however, might cause a toxic accumulation of the metabolite. A drug-controlled riboswitch could provide a second layer of control, allowing treatment to be adjusted when needed.

“You could just swallow a pill in the morning and then, over the day, get gene expression,” says Hartig. “If you don’t need it or have adverse effects, then you would not swallow your pill.”

Hartig says his group has tested related strategies in mouse models and hopes that the research will eventually support clinical applications.

Other researchers are combining multiple RNA switches to create more complex biological circuits. A team led by Jongmin Kim, a synthetic biologist at the Pohang University of Science and Technology in South Korea, has developed RNA-based ‘logic gates’ that activate genes only when specific combinations of signals are detected². These circuits work in a similar way to computer logic, applying decision-making rules to cellular signals.

For example, a gene could be activated only after several RNA switches have responded in the correct sequence. Kim’s circuits combine different RNA control technologies, including riboswitches that detect drugs or metabolites and ‘toehold switches’ that respond to specific RNA signals. The team is exploring whether these systems could be used to engineer therapeutic bacteria that reduce or prevent tissue damage in conditions such as inflammatory bowel disease.

RNA origami and the frontiers of molecular folding

The same base-pairing rules that create DNA double helices and RNA stems and loops can also be used to fold RNA into sophisticated nanoscale architectures. These structures could support next-generation vaccines, targeted therapies and new methods for controlling cellular behaviour.

Known as RNA origami, the approach builds on DNA origami³. DNA origami uses DNA strands to create structures ranging from basic geometric shapes to intricate flower-like designs. Earlier research by Zhang and others has shown that DNA-based nanostructures can be remarkably versatile and durable.

“It’s very stable, and it’s super robust,” says Zhang. But this stability has a limitation: after they are folded, DNA nanostructures are generally rigid and difficult to reconfigure.

RNA is more dynamic than DNA. Its flexibility enables it to adopt many different shapes and to remodel those structures in response to molecules or environmental changes. Zhang and her colleagues are investigating how these properties could be used to create responsive RNA nanodevices.

RNA origami remains a relatively young research field. Much of the work so far has involved designing and testing structures under tightly controlled laboratory conditions, but early findings are beginning to demonstrate its practical potential.

A team led by Hao Yan, a biochemist at Arizona State University, is studying RNA origami as a platform for developing a new type of cancer vaccine. The strategy is based on the immune system’s response to RNA outside cells. Because free RNA is often associated with viral infection, it can trigger immune receptors and produce a strong inflammatory response.

Yan and his colleagues have designed RNA origami structures that harness this response in a controlled way. The structures selectively activate immune receptors and cells, helping to stimulate dormant immune activity around a tumour⁴.

In mouse cancer models, the researchers linked the engineered RNA structures to additional immune-stimulating molecules. After injection, the treatment generated strong tumour-specific immune responses and improved survival.

“We’ve tried breast cancer, melanoma and a few other models, and it worked out well,” says Yan, who is preparing to move the research towards clinical testing.

Several research groups are also attempting to assemble RNA nanostructures inside living cells. This is a significant engineering challenge. RNA molecules begin folding almost as soon as they are transcribed, leaving little time for separately encoded strands to locate one another and assemble into larger structures. For this reason, many designs use a single RNA strand engineered to fold into the desired shape as it is produced, says Lorenzo Di Michele, a nanotechnologist at the University of Cambridge, UK.

Di Michele and other researchers have developed several ways to address this problem. One method uses RNA sequences that fold into simple lollipop-like structures, each made of a stem and a loop. These stem-loop units can be designed to interact through ‘kissing loops’, allowing them to form larger and more complex assemblies.

Using these and other RNA design principles, scientists can create genes that encode sequences capable of folding into two- or three-dimensional structures as the RNA is transcribed.

In research published last year⁵, Zhang and her colleagues used this strategy to produce RNA strands that self-assembled inside the nuclei of human cells. The resulting structures included zigzag scaffolds, rings and fishnet-like meshes. Zhang says the designs can be adjusted to control the structures’ size, shape and geometry.

“We could use this two-dimensional array to display different types of protein-binding domains, so we can harvest or enrich RNA-binding proteins in this environment,” says Zhang.

These RNA scaffolds could eventually support biosensors capable of monitoring gene expression in living cells in real time. They might also be designed to interact with chromosomes and regulate gene activity directly at its source.

RNA nanostructures that fold into a fluid

Other researchers are developing RNA nanostructures that mimic naturally occurring biological condensates. These assemblies contain proteins, nucleic acids and other molecules that cluster into fluid droplets while remaining separate from the surrounding cellular environment — much like oil droplets suspended in water.

Artificial condensates could create controlled microenvironments inside cells. By concentrating specific enzymes in one location, they might accelerate biochemical reactions. They could also coordinate the expression of groups of genes more precisely.

Because condensates are fluid rather than enclosed by a rigid physical barrier, they can potentially merge or separate as cellular conditions change. Their contents can also be redistributed, allowing the condensates to gather the ingredients required for a particular biochemical reaction.

Synthetic condensates can theoretically be built from many different types of molecules, although some are easier to engineer than others. Designing proteins that interact dynamically in complex ways requires precise control over their folding, a capability that remains largely beyond current scientific methods.