New vaccine technology enables researchers to determine where vaccines act in the body

The idea began, as breakthroughs often do, with frustration. The mRNA vaccine technology – known from the COVID-19 vaccines – works remarkably well, but the nanoparticles that transport the mRNA into cells often end up in the wrong places.

“They accumulate in the liver, are technically sensitive and give vaccine developers limited control,” explains one of the main authors behind the new vaccine technology, Camilla Foged, Professor at the Department of Pharmacy at the University of Copenhagen, Denmark.

The question arose as to whether the field had perhaps accepted too many compromises. Could a smarter structure be designed – and thereby achieve the same level of control over vaccines in the body that researchers already have over the mRNA code itself?

“This technology represents a step towards an overall goal of designing a vaccine that is more stable,” says Camilla Foged. “First-generation mRNA vaccines have some strengths, but they certainly also have weaknesses.”

She points in particular to the technical limitations.

“They are quite sensitive to physical stress,” she says. “This was already evident in the first versions, which required extreme cooling and were vulnerable during manufacture.”

From fragile delivery to controlled architecture

This combination of effective biology and fragile technology led the researchers to rethink particle design. Instead of relying solely on lipids, they chose to combine the particles with a biodegradable polymer, resulting in hybrid nanoparticles – partly a flexible lipid structure, partly a stabilising skeleton.

“Our idea was to design a slightly more stable version,” explains Foged. “We still use the lipids, which are the functional part and necessary for encapsulating and delivering the mRNA, but we also have a core based on a well-known, biodegradable polymer.”

The decisive turning point came when the researchers began to determine where the nanoparticles actually ended up in the body.

“What I find interesting about this system is that it remains at the injection site and does not end up in the liver, as many others do,” says Foged. “We want the vaccine to stay local and not distribute into the systemic circulation – so it does not spread throughout the body and causes systemic side effects,” she says, a principle that the results indicate can be achieved without compromising the immune response.

Animal studies have shown that the new hybrid structure delivers mRNA effectively, triggers a strong immune response and, in some cases, provides better protection than classic lipid nanoparticles in SARS-CoV-2 animal models. But for the researchers, the aim is not just to outperform existing technologies.

“We think of this as a platform technology,” says Foged. “It is about getting more options and more flexibility in the design – not about one solution fitting all.”

mRNA vaccines work – but the transport balls do not always

mRNA vaccines changed the world almost overnight when they formed the basis for the first COVID-19 vaccines. But the technology behind them – the nanoparticles that transport fragile mRNA strands into cells – still has fundamental limitations.

“The classical lipid nanoparticles – small fat-based transport balls around the mRNA – are effective but also surprisingly inflexible. They tend to accumulate in the liver, behave differently at different doses and leave vaccine developers with relatively few options for adjustment,” says Camilla Foged.

“They have some technical weaknesses – among other things, they are quite sensitive to physical stress,” she says.

This sensitivity manifests itself at several points in the process.

“For example, we saw that the first versions had to be stored at –80°C,” she says.

“And during production, they are sensitive to flow. Many processes use high flow to move the nanoparticles along, and lipid-based systems are more vulnerable in that regard.”

When delivery becomes vaccines’ greatest weakness

This tension has long been apparent to researchers in the field. The vaccines work – often spectacularly – but the delivery system (the actual transport of mRNA into the body and into cells) limits the choices researchers can make.

“They are obviously well suited for pandemic preparedness because they are so fast to develop,” says Foged.

Some describe it as building a house while the scaffolding is constantly moving. The need for better control became increasingly apparent.

This raised a more fundamental question among researchers working on the next generation of RNA technologies:

“I see mRNA vaccines as one type of vaccine that is good for certain things but also has some weaknesses,” says Foged.

What if delivery systems could be adjusted with the same precision as the mRNA sequence itself?

“We thought that if you can change the RNA part, you must also be able to change the carrier part,” says Foged. “Either you can change the RNA – or you can change the delivery system.”

A new particle architecture: lipid + polymer in one hybrid

Several groups therefore began to look beyond lipids alone. Some investigated polymers to achieve higher stability. Others experimented with hybrid structures. But bringing these ideas together into a single coherent platform that could simultaneously control stability, biodistribution (where in the body the particles end up) and immune activation proved difficult.

The hybrid nanoparticle platform seeks to fill precisely this gap in technology by systematically demonstrating how changes in particle architecture produce predictable biological effects. Not with a minor adjustment but with a new architecture: a particle made up of both lipids and a biodegradable polymer designed not only to transport mRNA but to give researchers new control over where it ends up, how long it stays there – and how the immune system is activated.

“We have thought of this as a platform technology,” says Foged. “Initially, we used SARS-CoV-2 as a model to show that it works – but the idea is that the platform can be used more broadly.”

For the researchers behind the work, the ambition is not to replace existing lipid nanoparticles but to expand the creative scope of vaccine development: to give the field more opportunities – more space to test, adjust and ask new questions.

And precisely this shift in thinking makes the work remarkable.

How they built the particles: microfluidics and systematic fine-tuning

The researchers approached the task like engineers building a machine from the inside out. Instead of starting with biology, they began with the structure: what physical properties should a truly adjustable delivery system have? Stability, predictability and the ability to remain at the injection site and enough flexibility that the composition can be changed without breaking the entire system.

“In this study, we systematically examined formulation and manufacturing parameters,” says Camilla Foged. “And it was more challenging than we actually expected – especially for mRNA. We already had experience with short RNA molecules, but the long mRNA molecules were much more difficult to work with.”

To investigate this systematically, the researchers used microfluidics – a micro-tube technology that enables nanoparticles to be produced with a high degree of control. Drop by drop, they varied polymer ratios, lipid compositions, solvents and flow rates, thereby creating a library of hybrid particles with different structures and properties.

“We use many components with very different physical and chemical properties,” explains Foged. “The polymer is quite hydrophobic, so there are issues with solubility, precipitation and structure that have been complex to understand and control.”

Inside the particles: a degradable core with a shell of lipids

At the centre of each particle is a biodegradable PLGA (poly(lactic-co-glycolic acid)) core – a well-known polymer used in medicine and implants – that protects the mRNA, surrounded by a lipid shell that enables uptake into cells. The researchers adjusted the content and organisation of lipids to influence crucial properties: how strongly the mRNA binds, how quickly it is released and how the particle interacts with immune cells.

“You might think that you could just swap one RNA for another,” says Foged.

“But mRNA is much more complex than short RNA molecules, which has required us to work very systematically.”

Each adjustment was followed by detailed measurements. The researchers analysed particle size, charge, morphology and encapsulation efficiency to identify formulations with clean and reproducible properties. This is where patterns began to emerge.

“We found that, depending on the formulation and manufacturing parameters, we get different structures,” says Foged. “And then it has been a matter of understanding how those structures affect the outcome.”

The big breakthrough: mRNA stays at the injection site

Promising candidates were then tested biologically. First in cell cultures, where researchers measured how effectively the formulations delivered mRNA and triggered protein expression. Next in mice, to investigate how the particles behaved in a living system – specifically, whether they remained at the injection site or were distributed systemically.

Finally, the most promising formulations were tested in a SARS-CoV-2 hamster model, a well-established system for investigating real protective immunity. This enabled them to compare the new hybrid platform directly with classic lipid nanoparticles – not only on molecular markers but on actual virus control.

“We have benchmarked against an mRNA vaccine that is comparable to Moderna’s SpikeVax vaccine,” says Foged. “The new version is at least as efficacious – and in some cases better.”

Throughout the process, the goal was not perfection but understanding: which structural elements are crucial? What adjustments can be made without losing functionality? And how can this knowledge give future vaccine developers greater freedom in their designs?

The answers came step by step – and pointed to something fundamentally new.

In animal models, the hybrid provided at least as strong – and sometimes better – protection

When the first series of hybrid nanoparticles came out of the microfluidics platform, something immediately caught the researchers’ attention: the mRNA stayed where it was placed. Unlike classic lipid nanoparticles, the hybrid particles remained at the injection site in mice.

This was confirmed by imaging and biodistribution studies – and for researchers who had struggled for years with unintended liver expression, it was a decisive breakthrough.

“This was actually one of the most surprising things,” says Camilla Foged. “We could see so clearly that the expression remained at the injection site and did not distribute to the liver.”

Functionally, the hybrid particles performed at least as well as established lipid nanoparticles. In mouse experiments, they efficiently delivered mRNA to antigen-presenting cells – immune cells that “show” the antigen – and triggered strong protein expression. Immunological measurements showed both strong antibody responses and clear T-cell responses, and several formulations matched the leading lipid nanoparticle benchmarks.

“We see robust immune responses, both humoral and cellular,” explains Foged.

“And it is completely on par with the lipid nanoparticles used today.”

More robust technology may mean easier handling – and perhaps fewer side-effects

However, the decisive turning point came in the SARS-CoV-2 hamster model, in which the researchers tested real protection against the virus. Here, the differences became clear. Hamsters vaccinated with the hybrid formulation showed:

• significantly lower virus loads in the lungs;
• reduced virus in the nasal cavity; and
• more effective overall protection than animals that had received a classic lipid nanoparticle formulation.

“We could see a clear reduction in the number of virus particles, especially in the nasal cavity,” says Foged, “but we do not yet have enough data to explain the mechanism behind it. And that is interesting, because it could potentially have implications for transmission.”

For Foged, the results directly confirmed that not only the chemistry but also the architecture shapes how mRNA vaccines work in the body.

“The structure matters,” she says. “When we change the architecture, we also change the biology.”

A platform and not a single vaccine: multiple design buttons for the next generation

In addition, the system proved to be more robust than classic lipid nanoparticles under conditions that normally challenge mRNA formulations.

“It would be great if it worked in larger animals and humans,” says Foged, “because then we might be able to avoid some systemic side-effects.”

This points to easier handling and potentially broader application in practice.

“This is not just about efficacy,” says Foged. “It is also about stability and control in the delivery system itself.”

Overall, the results point to a platform that combines high biological performance with structural predictability – a rare combination in a field in which delivery typically sets the limits for what vaccines can do.

“The next generation must be both better and safer,” says Foged. “And it is not enough for it to be a little better – it has to be much better.”

The next question: does it also work in larger animals – and in humans?

For the researchers behind the project, the hybrid nanoparticle platform is not an end-point but the beginning of a broader shift in how mRNA delivery is thought about. Teams are already investigating how the architecture can be adapted to different types of RNA, alternative routes of administration and entirely new vaccine concepts.

One of the most significant strengths is the system’s tunability – how finely it can be adjusted. The field has been largely dominated by a single particle type for almost all mRNA vaccines, but the hybrid approach enables much more precise tailoring of structure, stability, biodistribution and immune activation. This could be crucial for diseases in which targeting and balanced immune responses are critical.

“It gives us some design possibilities we have not had before,” explains Foged. “We can start adapting the particles to the biology instead of the other way around.”

What does this mean in practice – and what is still missing?

Another perspective is robustness and handling. The combination of polymer and lipid appears to make the system more resistant to the stresses that normally challenge mRNA vaccines. This allows for easier manufacture, transport, storage and potentially broader implementation.

“If we can make the systems more stable, it also changes how they can be manufactured and used in practice,” says Foged.

Nevertheless, there are still unanswered questions. How will the hybrid particles perform in larger animal models? Can production be scaled up reliably? And will the improved localisation also prove to be an advantage in clinical trials involving humans? These are now the key areas of focus for researchers and collaborators.

For Foged, however, the next phase is not just about data but about mindset.

“It is a bit naive to think that the mRNA vaccine technology was the answer to many problems in the vaccine field during the COVID-19 pandemic,” she says.

“For many years, we have accepted certain limitations in DNA/RNA delivery, and this work shows that it is possible to rethink the particles and gain more freedom as a researcher.”

If the platform continues to perform as the early results suggest, hybrid nanoparticles may prove to be an important step in the development of the next generation of RNA vaccines – a step towards a future in which design freedom, safety and efficacy are no longer opposites but intertwined.