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

Jun 12, 2025ACS applied materials & interfaces

Lipid Nanoparticles with Ionizable Sterols for Local mRNA Vaccine Delivery That Boosts Immune Cell Responses

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Abstract

ISL-3C-LNPs demonstrated high mRNA encapsulation and delivery efficiency.

Traditional lipid nanoparticles face challenges in liver-targeted transfection and cellular immune response activation.
CS22021-based ISL-3C-LNPs enable localized mRNA delivery at the injection site after intramuscular administration.
These LNPs may offer a better safety profile due to their localized delivery.
The CS22021-based formulation efficiently delivers a varicella-zoster virus mRNA vaccine, producing strong immune responses.
A significantly higher CD8T cell response is associated with the CS22021-based ISL-3C-LNP compared to conventional LNP formulations.

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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 CD8T cell response compared to a conventional LNP formulation, highlighting its potential in mRNA vaccine applications requiring enhanced CD8T cell activation, such as mRNA cancer vaccines. + +

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

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