Scientists at the University of Toronto have shown that the molecular structure of ionizable lipids in lipid-based nanoparticles plays a critical role in the translation efficiency of mRNA in the muscle, according to a study published in the Journal of American Chemical Society and featured in Science. The findings are a step towards the development of more effective mRNA vaccines and therapeutics.
The success of mRNA vaccines developed during the COVID-19 pandemic has highlighted the tremendous potential of mRNA as a new class of drugs. Since mRNA cannot penetrate the cell membrane by itself, lipid nanoparticles are used as vehicles for delivering mRNA to cells. A key component within the nanoparticle, the ionizable lipid, is the focus of the study.
“We argue that the ionizable lipid is the most important component because it not only affects the encapsulation of mRNA inside nanoparticles but also facilitates the release of mRNA inside cells,” says Dr. Omar Khan, assistant professor at the Institute of Biomedical Engineering at the University of Toronto and the Canada Research Chair in Nucleic Acid Therapeutics.
Grayson Tilstra and Julien Couture-Senécal, both Ph.D. candidates in Biomedical Engineering and co-lead authors of the study devised an engineering approach to iteratively optimize the molecular structure of new ionizable lipids based on a set of design criteria.
“The goal was to tune the chemistry bit by bit to understand the effect of small molecular changes on the performance of lipid nanoparticles,” says Tilstra.
Using this method, the authors discovered structure-activity relationships that differentiate ‘good’ from ‘bad’ ionizable lipids. This investigation could in turn inform other researchers about the kinds of ionizable lipids that are best suited for clinical use.
The study also investigated the effect of lipid dose on mRNA delivery.
“Our results show that below a certain lipid dose, nanoparticles lose quality and efficacy,” comments Couture-Senécal. “This dose threshold depends on the molecular structure of the ionizable lipid”.
Reducing the number of lipids per mRNA could reduce manufacturing costs and further improve the safety profile of lipid nanoparticles.
Dr. Khan and his group are now exploring the clinical potential of these new ionizable lipids and are working towards designing the next generation of lipid nanoparticles with better safety and efficacy.