RNA vaccine technology was critical to halting the COVID-19 pandemic and saving an estimated 2.5 million lives globally from late 2020 through October 2024. Since this success, scientists have been working to leverage RNA technology in a multitude of ways to address a myriad of diseases—in spite of the U.S. government’s decision to cut $500 million in mRNA vaccine research funding.
Now, RNA vaccine technology has just cleared two of its biggest hurdles. MIT engineers used AI to design a lipid nanoparticle formulation that lets RNA vaccines withstand months at room temperature, eliminating the need for deep-freeze storage. Meanwhile, scientists at Queen Mary University of London discovered a viral protein that lets self-amplifying RNA vaccines produce far more protein per dose—together pointing toward vaccines that are both easier to distribute and more powerful at lower doses.
Temperature-stable mRNA
In new research, MIT engineers have found a way to stabilize the lipid nanoparticles used to deliver RNA vaccines, allowing them to withstand months at high temperature without refrigeration. During the pandemic, the temperature requirements of mRNA vaccines created an initial cold storage nightmare. While advances and infrastructure have been put it place in the meantime, this research could make it easier to distribute RNA vaccines to regions without reliable cold chain storage.
The study, published in Nature Biotechnology, examined whether an AI algorithm could identify formulations of FDA-approved excipients—sugars, salts or polymers added to lipid nanoparticles—capable of stabilizing RNA vaccines at higher temperatures without altering the underlying particle structure used in COVID-19 vaccines from Moderna and Pfizer.
Researchers used the algorithm to analyze nearly 50 FDA-approved excipients, first measuring how well each stabilized mRNA encoding a bioluminescent protein when packaged into lipid nanoparticles. Five of the most promising excipients were then fed into the algorithm to predict ratios that would best stabilize particles similar to Moderna's formulation, with each round of lab testing feeding new data back into the model.
The process converged on a workable formulation within a few weeks. The resulting particles, packaged with COVID-19 mRNA antigens and vacuum-dried, remained stable after two months at 37 degrees Celsius, or a year at room temperature.
Mice vaccinated with these particles, even after long-term storage, mounted immune responses equivalent to those vaccinated with particles resembling the original Moderna formulation. The same heat-resistant formulation also worked in solid microneedle patches, and the algorithm successfully stabilized a separate lipid nanoparticle formulation resembling Pfizer's.
“The real beauty of this algorithm is that we can use it with small data sets,” said senior author Ana Jaklenec, a principal investigator at MIT's Koch Institute for Integrative Cancer Research. “It's really hard to run thousands of experiments, so this algorithm allows us to more easily achieve formulations with features that we want—in this case, stability.”
The researchers say the approach could extend beyond vaccines to other RNA-based therapeutics and drug-delivery platforms that require solid or heat-stable formulations. Once a heat-resistant formulation is developed for a given lipid nanoparticle, it could be adapted to deliver a wide range of mRNA payloads.
Making the vaccines more heat-tolerant could also help researchers drugs that could be administered through novel methods, such as microneedle patches. These patches contain hundreds of vaccine-filled microneedles, which dissolve when the patch is applied to the skin, releasing the vaccine.
Overcoming sRNA’s own weakness
Scientists at Queen Mary University of London discovered that adding a viral protein called NoV B2 helps overcome a fundamental flaw that has limited how much protein self-amplifying RNA (saRNA) vaccines can produce inside cells. The discovery could allow future vaccines to work at lower doses and reach more people, faster.
Unlike standard mRNA vaccines, which instruct cells to produce a protein that trains the immune system, saRNA copies itself once inside a cell. This self-replication process generates double-stranded RNA, which triggers the cell's natural antiviral defenses. Those defenses destabilize the saRNA and limit its ability to replicate and produce the protein needed to train the immune system. Ultimately, the barrier to saRNA vaccines lies within the technology itself.
In this study, published in Nature Communications, researchers found that adding NoV B2—a protein known to suppress RNA interference, one of the cell's natural defenses against double-stranded RNA—reduced how strongly cells restricted the saRNA. That allowed the saRNA to produce significantly more of its target protein in both stem cells and regular cells, without weakening its ability to stimulate the immune system.
By boosting how much protein saRNA can produce in the lab, the innovation opens new possibilities in gene therapy, cancer immunotherapy and protein replacement therapies. If translated successfully, this technology could make gene therapy safer and more affordable, make cancer vaccines more potent, and turn protein-replacement therapy from a process of repeated infusions to one in which the patient’s body generates its own medicine.
The team is now working to find a commercial partner capable of testing whether the approach translates successfully in vivo with the intent to move it toward clinical development.