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

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.