Researchers at Massachusetts Institute of Technology led by Robert S. Langer and Ana Jaklenec reported an artificial intelligence framework that discovered thermostable solid-state mRNA lipid nanoparticle vaccines retaining full potency after extended heat storage, according to a study published Sept. 28, 2026 in Nature Biotechnology. The formulations retained 100% bioactivity after storage at 37°C for more than 2 months and induced antigen-specific immune responses in animals that were non-inferior to freshly prepared vaccines.
The instability of mRNA-lipid nanoparticles (LNPs) necessitates ultra-cold storage, limiting global distribution and broader use in advanced delivery systems. Solid-state, water-free formulations enhance thermostability and enable integration into emerging delivery modalities such as microneedle patches. The authors reported that previous efforts to stabilize mRNA-LNPs have been constrained by narrow formulation scope and low-throughput screening methods.
The team developed Algorithm-Guided Experimental design for lipid Nanoparticle Thermostabilization (AGENT), a framework that couples high-throughput experimentation with Bayesian optimization to identify stable formulations from sparse experimental datasets. The paper described optimization in six iterations completed within 1 month, implemented within the AutODEx framework. The study tested two clinically relevant LNP compositions, an SM-102-based formulation representative of the Moderna composition and an ALC-0315-based formulation representative of the Pfizer-BioNTech composition, carrying mRNA encoding the SARS-CoV-2 receptor-binding domain (RBD sequence OP839194).
The optimized solid-state formulations preserved mRNA chemical integrity and LNP structure during heat storage, retaining 100% bioactivity after more than 2 months at 37°C. In rodents and non-human primates, the thermostable solid-state vaccines delivered intramuscularly induced antigen-specific immune responses non-inferior to those elicited by freshly prepared soluble vaccines, according to the paper. Water removal combined with an optimized excipient matrix protects LNPs in the solid state, preventing aggregation, fusion and chemical degradation during storage and preserving mRNA chemical integrity, LNP physicochemical structure and transfection potency.