YK-009 is a novel ionizable lipid for mRNA delivery. Comparisons of YK009-LNP-mRNA and commercial MC3-LNP-mRNA showed that YK009-LNP-mRNA vaccines had good biodistribution patterns, favorable tissue clearance, and high delivery efficiency. Furthermore, our study proved that YK009-LNP-Omicron mRNA could trigger a robust immune response and immune protection against the SARS-CoV-2 Omicron variant.