Structure–Function Correlation of Clinically Inspired Lipid Nanoparticles for Lung and Spleen Targeted mRNA Delivery

🥉 Top 5% JournalNov 27, 2025Advanced healthcare materials

How the design of lipid nanoparticles relates to their delivery of mRNA to the lungs and spleen

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Abstract

In vivo studies show that lipid nanoparticles with monoolein (MO) demonstrate enhanced mRNA expression compared to original Moderna formulations.

Lipid nanoparticles (LNPs) are a promising platform for mRNA delivery but face challenges like poor endosomal escape efficiency.
Incorporating monoolein (MO) as a helper lipid induces pH-dependent structural changes in LNPs that enhance mRNA release.
MO-based LNPs achieve superior mRNA transfection efficiency across various cell types, including lung macrophages, epithelial cells, and cancer cells.
Targeted delivery via intranasal and intravenous routes is validated for MO-based LNPs, improving mRNA expression in vivo.
A clear correlation between physicochemical properties and biological functions of LNPs is established, highlighting the role of the protein corona.

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Lipid nanoparticles (LNPs) have emerged as a transformative platform for mRNA delivery. However, challenges such as low endosomal escape efficiency remain key barriers in the field. Herein, we systematically investigate the clinically approved COVID-19 vaccine LNPs, extracting insights into physicochemical property-biological function relationships. Then we apply rational design principles to use monoolein (MO) as a structural helper lipid to replace phospholipid in Moderna LNP formulations. We reveal that MO incorporation induces pH-dependent mesophase transitions within LNPs with a protein corona, promoting inverse hexagonal mesophase structures that facilitate enhanced mRNA release and transfection. Comparison with COVID-19 vaccine LNPs confirms that MO-based LNPs achieve superior mRNA transfection efficiency across diverse cell types, including lung macrophages, epithelial cells, and cancer cells. Furthermore, in vivo studies validate enhanced mRNA expression of MO-based LNPs compared to the original Moderna LNPs, underscoring the capacity of both targeted pulmonary delivery by intranasal administration and targeted spleen delivery by intravenous administration. This study establishes a definitive physicochemical structure-biological function property correlation in LNP-mediated mRNA delivery, with the consideration of the protein corona effect on acidification-induced LNP internal mesophase evolution. This work provides guidance for the development of next-generation LNP platforms based on molecular biomedical engineering design principles.

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