Fluorinated Ionizable Lipids for Efficient Spleen-Targeted mRNA Delivery in Cancer Immunotherapy

Oct 29, 2025Journal of the American Chemical Society

Fluorinated Ionizable Lipids for Efficient mRNA Delivery Targeting the Spleen in Cancer Immunotherapy

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mRNA Technology on OpenScience ↗PubMed ↗DOI ↗

Abstract

SSC6F5 lipid nanoparticles achieve over 90% spleen-targeting specificity in various administration routes.

A library of 74 fluorinated ionizable lipids was synthesized to enhance mRNA delivery.
Intravenously administered SSC6F5 lipid nanoparticles resulted in 10.6-fold and 63.1-fold higher mRNA transfection in the spleen compared to existing formulations.
Proteomic analysis indicates a significant enrichment of apolipoprotein D and a reduction in apolipoprotein H on SSC6F5 lipid nanoparticles.
SSC6F5 lipid nanoparticles facilitated efficient genome editing in splenic immune cells in mouse models.
Significant tumor growth inhibition was observed in a melanoma model following treatment with SSC6F5 lipid nanoparticles.

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Efficient and selective mRNA delivery to immune-related organs, particularly the spleen, remains a major barrier to the broader clinical translation of mRNA therapeutics. Here, leveraging the clinically approved SM-102/ALC-0315 ionizable lipid scaffold, we rationally designed a combinatorial library of fluorinated ionizable lipids (FILs) by systematically modulating hydrophobic tails and fluorine stoichiometry. Through synthesis and evaluation of 74 candidate FILs, we identify SSC6F5 lipid nanoparticles (LNPs) as a lead formulation with exceptional spleen-targeting specificity (>90%) across intravenous, intramuscular, and subcutaneous administrations. Compared to clinically approved SM102 LNPs and spleen-tropic SM102/18PA (SORT) LNPs, intravenously administered SSC6F5 LNPs achieve 10.6-fold and 63.1-fold higher splenic mRNA transfection, respectively. Proteomic analysis of protein corona on SSC6F5 LNPs reveals significant enrichment of apolipoprotein D (Apod) and reduction in apolipoprotein H (Apoh), implicating a novel endogenous recognition pathway driving enhanced spleen targeting. Functionally, SSC6F5 LNPs enable efficient genome editing in splenic macrophages, dendritic cells, T cells, and B cells in Ai9 mice, and elicit potent CD8T cell and humoral responses in a B16-OVA murine melanoma model, resulting in significant tumor growth inhibition. These findings establish fluorinated lipids as a mechanistically distinct and translationally versatile platform for precision spleen-targeted mRNA delivery in gene editing and cancer immunotherapy. +