In mRNA vaccines, lipid nanoparticles (LNPs) act as delivery vehicles that protect fragile mRNA so that it can safely reach target cells and trigger an immune response. While these carriers are safe and scalable, their instability in liquid form limits shelf life and requires ultra-cold storage.
To improve stability, researchers have traditionally added excipients such as sugars, salts, or polymers to LNPs. Shifting to solid-state, water-free formulations extend thermostability, but previous efforts were limited by a narrow range of formulation options and slow screening processes.
Now, in a new study published in Nature Biotechnology, MIT engineers applied an AI-driven optimization framework to stabilize FDA-approved LNP formulations, specifically for the Moderna (SM-102-based) and Pfizer-BioNTech (ALC-0315-based) mRNA vaccines. These formulations helped retain 100 percent bioactivity at 37 degrees Celsius for over two months — eliminating the need for ultra-cold storage completely.
Developing stable RNA vaccine formulations
A successful solid-state mRNA-LNP formulation involves a labor-intensive process of finding suitable excipients and buffers, and then fine-tuning their specific ratios and concentrations. “In our experimental research, it’s impractical to run millions of experiments,” explained Ana Jaklenec, a principal investigator and senior coauthor of the study, to DDN. “We needed a model that could work with a relatively small data set and didn’t have to perfectly understand the entire formulation space — just the specific problem we wanted to solve.”
To address this challenge, the team created the Algorithm-Guided Experimental Design for Lipid Nanoparticle Thermostabilization (AGENT) platform. AGENT couples high-throughput experimentation with Bayesian optimization, using a Gaussian process model to analyze patterns in experimental outcomes and predict promising formulation candidates. To evaluate payload protection, the researchers packaged mRNA encoding a bioluminescent protein into the candidate formulations and delivered them into cells; light emission served as a direct measure of preserved mRNA activity.
By continuously learning from incoming data, the AI model “kept using that information to optimize where the excipients should be,” Jaklenec noted. Within six iterative rounds, the platform achieved 100 percent formulation stability and identified an optimal candidate for preclinical animal trials.
To test heat resistance, the team packaged FDA approved COVID-19 mRNA antigens in the new LNP formulation, vacuum dried, and stored them at 37 degrees Celsius for two months or at room temperature for a year.
Mice vaccinated with these long-stored particles showed immune responses equivalent to those given freshly prepared vaccines.
These results underscore the potential of AI-optimized, solid-state mRNA formulations to overcome cold-chain barriers. Mechanistically, the excipient matrix immobilizes the LNPs, preventing degradation, and additional components, such as salts, further shield the mRNA payload from oxidation.
“It’s essentially like freezing, but at room temperature,” Jaklenec explained.
Microneedle patch delivery may expand vaccine access
The AI-optimized thermostable formulations were also adapted for microneedle patch delivery and proved effective in both rodent and nonhuman primate models, producing immune responses comparable to traditional liquid injections.
These small patches contain arrayed dissolvable needles loaded with the vaccine in solid form. “It’s like a dry, prickly bandage,” Jaklenec explained. Applied to the skin, the microscale tips pierce the outer dermal layer painlessly and dissolve, releasing the payload directly into the tissue.
Beyond eliminating liquid handling, storing the formulation within a solid microneedle matrix further stabilizes the mRNA–LNPs at elevated temperatures, preserving potency without refrigeration. The result is a vaccine delivery strategy that enables easy transport, hassle-free storage, and simplified administration.
In the future, pairing shelf-stable solid formulations with microneedle manufacturing could open possibilities for decentralized production. As Jaklenec put it, “It would give people the independence to do that locally if they needed to and wouldn’t have to rely on these large companies.”
