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

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Molecular Biology

Background:

• Lipid nanoparticles (LNPs) are crucial for mRNA delivery, but endosomal escape remains a challenge.
• Understanding physicochemical properties of LNPs is key to improving mRNA delivery efficiency.

Purpose of the Study:

• To investigate clinically approved COVID-19 vaccine LNPs and their structure-function relationships.
• To rationally design novel LNPs using monoolein (MO) as a helper lipid to enhance mRNA delivery and transfection.

Main Methods:

• Systematic investigation of COVID-19 vaccine LNPs.
• Incorporation of monoolein (MO) into LNP formulations.
• Analysis of pH-dependent mesophase transitions and protein corona effects.
• In vitro transfection assays across diverse cell types.
• In vivo mRNA expression studies following intranasal and intravenous administration.

Main Results:

• Monoolein incorporation induced pH-dependent mesophase transitions, favoring inverse hexagonal structures.
• MO-based LNPs demonstrated superior mRNA transfection efficiency compared to original Moderna LNPs.
• Enhanced in vivo mRNA expression was observed in lung and spleen after intranasal and intravenous delivery, respectively.
• Established a physicochemical structure-biological function correlation for LNP-mediated mRNA delivery, considering protein corona effects.

Conclusions:

• Monoolein is a promising helper lipid for developing advanced LNP platforms for mRNA delivery.
• The study provides a molecular biomedical engineering design framework for next-generation LNPs.
• Understanding LNP internal mesophase evolution under physiological conditions is critical for optimizing mRNA therapeutics.