One‐Component Cationic Lipids for Systemic mRNA Delivery to Splenic T Cells

Unlocking the full potential of mRNA immunotherapy necessitates targeted delivery to specific cell subsets in the spleen. Four‐component lipid nanoparticles (LNPs) utilized in numerous clinical trials are primarily limited in hepatocyte and muscular targeting, highlighting the imperative demand for targeted and simplified non‐liver mRNA delivery systems. Herein, we report the rational design of one‐component ionizable cationic lipids to selectively deliver mRNA to the spleen and T cells with high efficacy. Unlike the tertiary amine‐based ionizable lipids involved in LNPs, the proposed cationic lipids rich in secondary amines can efficiently deliver mRNA both in vitro and in vivo as the standalone carriers. Furthermore, these vectors facilitate efficacious mRNA delivery to the T cell subsets following intravenous administration, demonstrating substantial potential for advancing immunotherapy applications. This straightforward strategy extends the utility of lipid family for extrahepatic mRNA delivery, offering new insights into vector development beyond LNPs to further the field of precise mRNA therapy. Unlike conventional four‐component lipid nanoparticles (LNPs) that predominantly target the liver and possess complex constituents, we designed simplified one‐component ionizable cationic lipid/mRNA nanoparticles (CLNs) for extrahepatic mRNA delivery. These CLNs facilitated mRNA expression in the spleen and T cells, demonstrating substantial potential for immunotherapy applications.