In response to the SARS-CoV-2 pandemic, mRNA vaccines prepared with lipid nanoparticles (LNPs) have been rapidly developed and deployed. Because of the unstable nature of mRNA, the identification of impurities that may affect the stability and efficacy of the product is very important for the long-term use of nucleic acid drugs. Hence, reversed-phase ion pair high performance liquid chromatography (RP-IP HPLC) was used to identify a class of impurities formed by lipid-mRNA reaction, which cannot be detected by traditional mRNA purity analysis technology.

Nucleic acid-based drugs have become a promising alternative to traditional vaccines and treatments. Most notably, the mRNA-based vaccines recently developed by Pfizer-BioNTech and Moderna changed the course of the SARS-CoV-2 pandemic and quickly received emergency use authorization for public use because of the effectiveness and safety shown in Phase III trials. The rapid deployment of these vaccines is partly due to the advantages of mRNA over traditional vaccines, including the flexibility of mRNA sequence design and the scalability of the manufacturing process.

In addition, from the point of view of safety and pharmacokinetics, the rapid biodegradability of mRNA makes it an attractive way; however, this inherent instability also effectively provides the key shelf-life limiting parameters and obstacles of the vaccine through various administration routes.

Effective delivery of mRNA-based vaccines and treatments is achieved through lipid nanoparticles (LNPs), which can protect nucleic acid degradation by exogenous and endonuclease and promote cell uptake and expression. The delivery system is particularly effective for Pfizer-BioNTech and Moderna COVID-19 vaccines because it takes advantage of the surface properties of London ribonucleic acid, the ability of LNP to promote internal escape by aminolipid ionization, and tissue-specific mRNA delivery based on particle size. These characteristics together improve the immunogenicity of the vaccine.

Although LNP technology is an effective way to transfer mRNA to tissue, the interaction of some chemical functions during storage, such as oxidation, hydrolysis, or transesterification, may lead to mRNA degradation by splitting the skeleton of mRNA into smaller fragments.

A paper entitled “A novel mechanism for the loss of mRNA activity in lipid nanoparticle delivery systems” published in Nature Communication reports the discovery, characterization, and identification of another type of mRNA reactivity that leads to loss of activity, and the formation of lipid-mRNA adducts by covalent addition of reactive lipid species to nucleic acid groups. Importantly, since many lipid-based nucleic acid preparations share common chemical functions, especially those that use ionizable amino acids-lipids, the mechanisms identified in this study are widely applicable. These data can inform production programs to limit the formation of lipid-mRNA adducts and ensure the high quality of nucleic acid-based products.