Journal of controlled release : official journal of the Controlled Release SocietyOct 22, 2026

How ionizable lipids affect mRNA vaccine makeup and immune response

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗

Updated Oct 23, 2026

Abstract

Five ionizable lipids were evaluated for their impact on lipid nanoparticle organization and mRNA delivery.

Physiochemical analysis indicated the potential coexistence of liquid crystalline lamellar and inverse hexagonal phases in lipid nanoparticle formulations.
Ionizable lipids with saturated, multi-tail structures, such as Lipid-5 and SM-102, enhanced endosomal fusion and resulted in increased protein expression in vivo.
In contrast, lipids like cKK-E12, which formed lamellar-like structures, exhibited reduced encapsulation efficiency and transfection potency.
All formulations induced robust binding and neutralizing antibody responses, but responses were lower in formulations using Lipid-5 and SM-102 compared to others.
Protein expression levels did not correlate with antibody titers, suggesting efficient antigen expression may not predict humoral immunity.

Simplified

The COVID-19 pandemic disrupted global supply chains, causing shortages of critical lipid-based raw materials for mRNA vaccine production. To enhance formulation resilience, we systematically evaluated the impact of five ionizable lipids (ILs) on lipid nanoparticle (LNP) organization, mRNA delivery and immunogenicity. The physiochemical analysis revealed the potential coexistence of liquid crystalline lamellar (L_α) and inverse hexagonal (H_II) phases, or a mixture of nucleotide-loaded and non-loaded H_II phases within developed LNP formulations. Furthermore, ILs with saturated, multi-tail structures, such as Lipid-5 and SM-102, favored inverse hexagonal (H_II) internal organization and fusion intermediates, correlating with enhanced endosomal fusion and higher in vivo protein expression. In contrast, ILs such as cKK-E12, which featured dual ionization headgroups and tended to form lamellar-like structures, showed reduced encapsulation efficiency and transfection potency. The preclinical experiments demonstrated that all developed formulations induced robust binding and neutralizing antibody responses; however, antibody responses were lower in mRNA Lipid 5 LNPs and mRNA SM-102 LNPs than in other formulations. Notably, within the limited panel of ILs in this study, protein expression levels did not show a clear correlation with antibody titers, highlighting that efficient antigen expression alone is not predictive of humoral immunity. These findings underscore how IL structural features influence LNP architecture and function, informing the rational design of next-generation mRNA vaccines.

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How ionizable lipids affect mRNA vaccine makeup and immune response

Abstract

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