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Updated: Sep 23, 2025
Using Lipid Nanoparticles for the Delivery of Chemically Modified mRNA into Mammalian Cells
Published on: June 10, 2022
An imidazole modified lipid confers enhanced mRNA-LNP stability and strong immunization properties in mice and
Manon Ripoll1, Marie-Clotilde Bernard2, Céline Vaure2
1Sanofi R&D, Campus Mérieux, 1541 avenue Marcel Mérieux, 69280, Marcy l'Etoile, France; Laboratoire de Conception et Application de Molécules Bioactives, Equipe 3Bio (Biovectorisation, Bioconjugaison, Biomatériaux), UMR 7199 - CNRS/Université de Strasbourg, Faculté de Pharmacie, 74 route du Rhin, BP 60024, 67401, Illkirch Cedex, France.
Abstract:
The mRNA vaccine technology has promising applications to fight infectious diseases as demonstrated by the licensing of two mRNA-based vaccines, Comirnaty® (Pfizer/BioNtech) and Spikevax® (Moderna), in the context of the Covid-19 crisis. Safe and effective delivery systems are essential to the performance of these vaccines and lipid nanoparticles (LNPs) able to entrap, protect and deliver the mRNA in vivo are considered by many as the current "best in class". Nevertheless, current mRNA/LNP vaccine technology has still some limitations, one of them being thermostability, as evidenced by the ultracold distribution chain required for the licensed vaccines. We found that the thermostability of mRNA/LNP, could be improved by a novel imidazole modified lipid, DOG-IM4, in combination with standard helper lipids. DOG-IM4 comprises an ionizable head group consisting of imidazole, a dioleoyl lipid tail and a short flexible polyoxyethylene spacer between the head and tail. Here we describe the synthesis of DOG-IM4 and show that DOG-IM4 LNPs confer strong immunization properties to influenza HA mRNA in mice and macaques and a remarkable stability to the encapsulated mRNA when stored liquid in phosphate buffered saline at 4 °C. We speculate the increased stability to result from some specific attributes of the lipid's imidazole head group.
