Each virus wraps its genetic material inside a precisely shaped protein shell, often made of hundreds or thousands of pieces that somehow find each other and lock into place without any instructions. Now, researchers at the University of Oxford found a way to watch this assembly happen in real time, molecule by molecule. Their findings, published in Nature, could help pave the way for new antiviral drugs and better vaccines.
The Puzzle of Self-Assembly
Viruses face a construction challenge that would baffle any engineer. Their outer shells (called capsids) can contain huge numbers of protein components, yet these pieces spontaneously snap together into the right shape, every single time.
Scientists have been puzzling over this process for decades, but catching the stages in between (half-finished virus particles) is extremely hard. Most experiments can show what’s there at the start and the end, but not how one becomes the other.
Co-lead author Dr Roi Asor, from the Department of Chemistry and Kavli Institute for Nanoscience Discovery at Oxford, put it this way: “A virus has to solve an extraordinary construction problem. Its components somehow have to find the right arrangement among a huge number of possibilities, without a blueprint or machinery directing the process. We can now watch what happens molecule by molecule and see the physical rules that make it possible.”
Weighing a Virus as It Grows
To tackle the problem, the Oxford team used an engineered virus-like particle made of 60 protein pieces. They combined a technology called mass photometry (developed at Oxford, it measures the mass of single molecules by analysing the light they scatter) with a new technique that holds individual molecules in place so they can be observed continuously.
As a result, they could effectively “watch” a single virus grow, by weighing it again and again as new proteins joined it. Co-first author Dan Loewenthal, a PhD student at Oxford, explained the appeal of the method simply: “This method lets us study the assembly process directly, we just take a video!”
A Maze With Locking Doors
What they saw was like watching someone find their way through a maze. The protein pieces initially stick together with only weak, reversible connections. If an arrangement isn’t right, the pieces fall apart and try again. It’s trial and error at the molecular level.
But every so often, a few pieces come together in a particular closed shape, held in place by multiple strong connections at once. These stable intermediate forms act like checkpoints along the way. Once the pieces reach a checkpoint, they’re locked in and can keep building from there.
A key moment comes when five of the larger protein building blocks join to form a closed pentagonal ring. This is the first truly stable structure in the pathway, and from that point on, the process speeds up: fewer new proteins are needed to reach each successive milestone.
Co-lead author Professor Philipp Kukura (also from the Department of Chemistry and Kavli Institute for Nanoscience Discovery) said: “Until now, much of our understanding of how these structures assemble has had to be reconstructed from snapshots or theoretical models. Being able to both quantify the underlying interactions and follow one particle as it grows changes that. We can see the important intermediate structures appear and deduce a detailed model of the construction process.”
Why Mistakes Matter
The weak initial connections turn out to be essential, not a flaw. Dr Asor explained: “The weak interactions give the system room to make mistakes. Most encounters don’t have to be successful: the components can separate and try again. But once enough of them come together in the right closed arrangement, the structure becomes stable and assembly can move forward. That combination of trial and error followed by locking in successful structures is what makes the process so reliable.”
From Viruses to Vaccines and Beyond
Understanding how viruses build themselves could open new doors for medicine. If scientists know exactly how a viral shell assembles, they can design drugs to disrupt that process, or they can engineer vaccines and therapeutic particles that assemble in similar ways.
Co-author Dr Jack Tan noted: “The ability to understand these processes at the molecular level could have important applications in vaccine development and antivirals that disrupt viral assembly.”
The approach could also stretch far beyond viruses. Self-assembly is a core process in biology, from the scaffolding inside cells to the small compartments that house crucial reactions. By watching the process happen one molecule at a time, the Oxford team has given biologists a powerful new lens for understanding how life builds itself.
Asor, R., Loewenthal, D., Tan, J., Kukura, P. et al. (2026). Molecular-level observation of the self-assembly of a virus-like particle. Nature. DOI: 10.1038/s41586-026-10948-z