Bottom-up fabrication of lipid nanoparticles with low permeability

Research Project, 2024 – 2027

Lipid nanoparticles are used as the delivery platform for the Pfizer-BioNTech and Moderna vaccines against COVID. These vaccines are currently kept at ultra-low temperatures, with some formulations requiring shipment and storage between –90 °C and –60 °C. At higher temperatures, the mRNA is susceptible to decomposition via hydrolysis, which dramatically reduces efficacy. Drawing inspiration from extremophile archaea organisms, we propose to incorporate macrocyclic lipids into lipid nanoparticles to reduce particle permeability and improve mRNA stability. The challenge is that these macrocyclic lipids are exceptionally difficult to synthesize in the laboratory; their biosynthesis is poorly understood; and they must generally be harvested directly from archaea organisms. In this project, we will synthesize macrocyclic lipids by folding linear precursors under confinement to encourage cyclization instead of polymerization. Similar to the lipids used in the COVID vaccines, the macrocyclic lipids synthesized during this project will form a protective layer around the mRNA. The resulting particles are anticipated to protect mRNA from water, oxygen, and changes in pH, thus increasing the required shipping and storage temperature for mRNA therapies. This project will have widespread implications, as oligonucleotide therapies will soon be used to treat genetic diseases, and these therapies will be less expensive and more accessible if they can be kept at normal temperatures.