Ionizable Sterol Lipid-Based Three-Component Lipid Nanoparticles for Localized Delivery of mRNA Vaccine with Stronger Cellular Immune Responses

Lipid nanoparticles (LNPs) have shown great promise for nucleic acid drug delivery. Canonical LNPs consist of four lipid components: ionizable lipid, cholesterol, Polyethylene glycol-yl-lipid (PEGyl-lipid), and phospholipid. However, these traditional LNPs face limitations in mRNA vaccine delivery, including liver-targeted transfection and the insufficient activation of cellular immune responses. A more efficacious and safer LNP system remains a great challenge. Herein, we report ionizable sterol lipid-based three-component LNPs (ISL-3C-LNPs), which exhibit high mRNA encapsulation and delivery efficiency. Among these, CS22021-based ISL-3C-LNP demonstrated localized mRNA delivery at the injection site following intramuscular administration, which potentially contributes to a good safety profile. Moreover, the CS22021-based ISL-3C-LNP enabled the efficient delivery of a varicella-zoster virus (VZV) mRNA vaccine by eliciting robust humoral and cellular immune responses. Notably, it elicited a significantly higher CD8⁺T cell response compared to a conventional LNP formulation, highlighting its potential in mRNA vaccine applications requiring enhanced CD8⁺T cell activation, such as mRNA cancer vaccines.