Journal of controlled release : official journal of the Controlled Release SocietyJun 3, 2025

How the fat structure in ionizable lipids affects mRNA delivery and immune response of lipid nanoparticles

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗

Updated Apr 1, 2026

Abstract

A library of 17 ionizable lipids was synthesized to explore the effects of tail unsaturation on mRNA lipid nanoparticles.

Tail unsaturation may influence the physicochemical properties of lipid nanoparticles.
Enhanced endosomal escape and mRNA delivery efficiency could be associated with specific degrees and types of unsaturation.
Modulating tail unsaturation is linked to changes in the immunogenicity of lipid nanoparticles in vivo.
Findings suggest that optimizing tail unsaturation could improve mRNA encapsulation and delivery efficacy.
The study used interleukin-27 (IL-27)-encoded mRNA as a model to demonstrate potential for protein supplementation therapies.

Simplified

Ionizable lipids are critical for determining the potency of mRNA lipid nanoparticles (LNPs). Various mRNA therapies require LNPs that achieve efficient delivery while maintaining appropriate immunogenicity in vivo. While research has largely focused on screening the amine headgroups, linkers and hydrophobic tails of ionizable lipids, the role of tail unsaturation in influencing mRNA delivery and immunogenicity of LNPs has received less attention. Here, we utilized a four-component Ugi reaction (Ugi-4CR) system to synthesize a small library of 17 ionizable lipids with identical backbones but varying in degrees, positions, and types of unsaturation in hydrophobic tails. We systemically investigated structure-activity relationships and elucidated the influence of tail unsaturation on physicochemical properties, endosomal escape, mRNA delivery efficiency and immunogenicity of LNPs. The findings indicate that optimization of tail unsaturation could serve as a promising strategy to improve mRNA encapsulation and delivery efficacy while modulating LNP immunogenicity in vivo. Using interleukin-27 (IL-27)-encoded mRNA as a model, we demonstrated the potential of selected LNPs for protein supplementation therapies. These insights provide a foundation for the rational design of ionizable lipids, advancing the development of more efficient and safer mRNA delivery systems.

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Declaration of competing interest The authors declare no competing interests.

PubMed

How the fat structure in ionizable lipids affects mRNA delivery and immune response of lipid nanoparticles

Abstract

Full Text

Funding

Competing interests

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Abstract

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