Novel Ionizable Lipid Nanoparticles for SARS‐CoV‐2 Omicron mRNA Delivery

mRNA‐based therapy has emerged as the most promising nucleic acid therapy in the fight against COVID‐19. However, a safe and efficacious systemic delivery remains a challenge for mRNA therapy. Lipid nanoparticles (LNPs) are currently widely used in mRNA delivery vehicles. Here, a series of ionizable LNPs is rationally designed. YK009‐LNP is an optimal delivery platform to carry mRNA. YK009‐LNP exhibits higher mRNA delivery efficiency, a more favorable biodistribution pattern, and better safety than the approved MC3‐LNP. In addition, mRNA encoding severe acute respiratory syndrome coronavirus 2 Omicron receptor binding domain protein is synthesized and intramuscular administration of mice with YK009‐LNP‐Omicron mRNA induces a robust immune response and immune protective effect. A novel mRNA delivery vehicle with more powerful delivery efficiency and better safety than the approved LNPs is provided here. A novel ionizable lipid YK009 is developed for lipid nanoparticles (LNP) formulation. YK009, DSPC, cholesterol, and DMG‐PEG 2000 are mixed with mRNA by a microfluidic‐based procedure to form YK009‐LNP‐mRNA. The YK009‐LNP‐SARS‐CoV‐2 Omicron mRNA vaccine could trigger a robust humoral immune response and cellular immune response and immune protection against the SARS‐CoV‐2 Omicron variant in mice.