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However, challenges such as low endosomal escape efficiency remain key barriers in the field. Herein, we systematically investigate the clinically approved COVID\u201019 vaccine LNPs, extracting insights into physicochemical property\u2010biological 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\u2010dependent mesophase transitions within LNPs with a protein corona, promoting inverse hexagonal mesophase structures that facilitate enhanced mRNA release and transfection. Comparison with COVID\u201019 vaccine LNPs confirms that MO\u2010based 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\u2010based 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\u2010biological function property correlation in LNP\u2010mediated mRNA delivery, with the consideration of the protein corona effect on acidification\u2010induced LNP internal mesophase evolution. This work provides guidance for the development of next\u2010generation LNP platforms based on molecular biomedical engineering design principles.<\/jats:p>","DOI":"10.1002\/adhm.202503612","type":"journal-article","created":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T07:50:07Z","timestamp":1764229807000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Structure\u2013Function Correlation of Clinically Inspired Lipid Nanoparticles for Lung and Spleen Targeted mRNA Delivery"],"prefix":"10.1002","volume":"15","author":[{"given":"Natalia","family":"Martinez","sequence":"first","affiliation":[{"name":"Molecular Assembly Laboratory School of Science STEM College RMIT University  Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haitao","family":"Yu","sequence":"additional","affiliation":[{"name":"Molecular Assembly Laboratory School of Science STEM College RMIT 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