Cost-effective yet high-performance ionizable lipids for mRNA-lipid nanoparticle vaccines

May 24, 2025Biomaterials

Affordable and effective ionizable lipids for mRNA vaccine nanoparticles

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mRNA Technology on OpenScience ↗PubMed ↗DOI ↗

Abstract

A library of 161 ionizable lipids led to the identification of six novel lipids that enhance mRNA vaccine delivery and immune response against SARS-CoV-2.

R2- and R3-based lipid nanoparticles induce higher antibody titers and stronger cellular immune responses in mice compared to R1-based nanoparticles.
The R2U2- and R3U2-based nanoparticles enhance specific immune responses, including increased IFN-γ production and activation of TNF-α CD4/CD8 T cells.
These novel lipid nanoparticles also improve dendritic cell activation and retention in lymph nodes.
The immune responses and safety profiles of R2U2-based lipid nanoparticles are comparable to those of the commercial ALC-0315-based nanoparticles.
R2U2-based lipid nanoparticles administered intranasally and intratracheally increase mucosal immunity, indicated by elevated sIgA levels in mice.
Further evaluation in cynomolgus macaques demonstrates the efficacy of this lipid nanoparticle system for potential cost-effective mRNA vaccine development.

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Ionizable lipids (ILs) are critical components in mRNA vaccines, which have been instrumental in the global response to SARS-CoV-2. However, current commercialized ILs in mRNA vaccines are typically synthesized through multiple-step organic reactions, complicating quality control and driving up production costs. To address this, we have developed novel ILs by a one-pot Ugi four-component reaction (Ugi-4CR), significantly simplifying synthesis while maintaining high yields and reducing costs. Here, from a library of 161 ILs, we chose six ILs with high expressing luciferase and investigated their performance in delivering the mRNA vaccine of SARS-CoV-2. These ILs feature distinct ionizable heads, N,N-dimethylethyl (R1), N,N-dimethylpropyl (R2), and N,N-diethylpropyl (R3), paired with hydrophobic tails of varying unsaturation, cis-9-octadecenoic (U1) and (9Z,12Z)-9,12-octadecadienoic (U2), respectively. In murine models, R2-and R3-based mSpike-LNPs induce higher antibody titers and stronger cellular immune responses compared to the R1-based counterparts, suggesting their superior mRNA delivery and expression efficiency. Notably, R2U2- and R3U2-based mSpike-LNPs further enhance IFN-γsplenocyte responses and activation of TNF-αCD4/CD8T cells, coupled with improved dendritic cell activation and retention in lymph nodes. We confirm that the R2U2-based LNPs on different mRNA antigens exhibit immune responses and safety profiles comparable to the commercial ALC-0315-based LNPs. Moreover, intranasal and intratracheal administration of R2U2-based mSpike-LNPs enhances mucosal immunity, as evidenced by elevated sIgA levels in mice. Further evaluation in cynomolgus macaques proves the efficacy of this LNP system, highlighting its potential for developing cost-effective mRNA vaccines. + + + +

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Cost-effective yet high-performance ionizable lipids for mRNA-lipid nanoparticle vaccines

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