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

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.