Retinoic-Acid-Derived Ionizable Lipids Enable Spleen-Selective Antigen Expression for mRNA Cancer Vaccination

Area of Science:

• Biotechnology
• Immunology
• Drug Delivery

Background:

• Effective mRNA cancer vaccination depends on antigen expression in lymphoid antigen-presenting cells.
• Current mRNA delivery systems may lack spleen selectivity and can cause unwanted inflammation.

Purpose of the Study:

• To develop a spleen-selective ionizable lipid platform for enhanced mRNA expression in antigen-presenting cells.
• To engineer retinoic-acid-derived ionizable lipids (RAILs) for targeted mRNA delivery and improved cancer vaccination.

Main Methods:

• Systematic variation of ionizable lipid scaffolds, linkers, and retinoid-derived hydrophobic domains to create a 40-member RAIL library.
• In vitro and in vivo screening of lipid nanoparticles (LNPs) for spleen-selective reporter expression and functional mRNA delivery.
• Evaluation of LNP formulations in reporter mice and a B16F10-OVA tumor challenge model.

Main Results:

• Identified AT4-13CRA LNPs as the lead formulation with significantly higher spleen-to-liver mRNA expression compared to SORT formulations.
• AT4-13CRA LNPs demonstrated reduced lysosomal mRNA retention and attenuated TNF-α/NF-κB activation.
• Enhanced antigen-specific CD8+ T-cell and antibody responses, leading to improved prophylactic protection against tumors.

Conclusions:

• Retinoid-derived hydrophobic-domain engineering provides a chemically defined strategy for spleen-selective mRNA delivery.
• This approach enables inflammation-restrained, antigen-presenting-cell-centered mRNA cancer vaccination.
• AT4-13CRA LNPs represent a promising platform for advancing mRNA cancer immunotherapy.