Lipid nanoparticles, known as LNPs, have been the primary delivery system used in mRNA vaccines. Since the approval of the first LNP therapy, Onpattro, numerous studies have researched and improved the components of the LNP formulation, particularly the ionisable cationic lipids and PEG lipids. Thanks to these advancements, we now have two FDA-approved COVID-19 mRNA vaccines: mRNA-1273 and BNT162b2, produced by Moderna and Pfizer-BioNTech, respectively. However, no study has yet compared the effectiveness of the ionisable cationic lipids versus the PEG lipids against the latest strains of the SARS-CoV-2 virus. Our team's previous research has shown that the delivery and expression of mRNA in the secondary lymphoid organs play crucial roles in triggering an adaptive immune response from LNP-mRNA vaccines1. Additionally, our team has developed a membrane-anchored receptor binding domain (RBD-TM) COVID-19 LNP mRNA vaccine that can overcome the immune imprinting effect2. This upcoming study aims to compare the gene expression of different ionisable cationic lipids, such as DLin-MC3-DMA, SM102, and ALC0315, and their respective humoral immune responses against the RBD of XBB.1.5 of the SARS-CoV-2 virus. This research has the potential to influence future vaccine development.