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Lipid nanoparticles (LNPs) tailored for mRNA delivery were optimized to serve as a platform for treating metabolic diseases. Four distinct lipid mixes (LMs) were formulated by modifying various components: LM1 (ALC-0315/DSPC/Cholesterol/ALC-0159), LM2 (ALC-0315/DOPE/Cholesterol/ALC-0159), LM3 (ALC-0315/DSPC/Cholesterol/DMG-PEG2k), and LM4 (DLin-MC3-DMA/DSPC/Cholesterol/ALC-0159). LNPs exhibited stability and homogeneity with a mean size of 75 to 90 nm, confirmed by cryo-TEM and SAXS studies. High mRNA encapsulation (95–100%) was achieved. LNPs effectively delivered EGFP-encoding mRNA to HepG2 and DC2.4 cell lines. LNPs induced cytokine secretion from human peripheral blood mononuclear cells (PBMCs), revealing that LM1, LM2, and LM4 induced 1.5- to 4-fold increases in IL-8, TNF-α, and MCP-1 levels, while LM3 showed minimal changes. Reporter mRNA expression was observed in LNP-treated PBMCs. Hemotoxicity studies confirmed formulation biocompatibility with values below 2%. In vivo biodistribution in mice post intramuscular injection showed significant mRNA expression, mainly in the liver. The modification of LNP components influenced reactogenicity, inflammatory response, and mRNA expression, offering a promising platform for selecting less reactogenic carriers suitable for repetitive dosing in metabolic disease treatment.
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; Huck-Iriart, Cristián 3
; Svensson, Malin 1 ; Fraude, Silvia 1
; Pretsch, Leah 1 ; Si, Shutian 4 ; Lieberwirth, Ingo 4 ; Gehring, Stephan 1 ; Cacicedo, Maximiliano 1 ; Germán Abel Islan 2 1 Children’s Hospital, University Medical Center of the Johannes, Gutenberg University, Langenbeckstr. 1, 55131 Mainz, Germany;
2 Children’s Hospital, University Medical Center of the Johannes, Gutenberg University, Langenbeckstr. 1, 55131 Mainz, Germany;
3 Instituto de Tecnologías Emergentes y Ciencias Aplicadas (ITECA), Universidad Nacional de San Martín (UNSAM)-CONICET, Escuela de Ciencia y Tecnología (ECyT), Laboratorio de Cristalografía Aplicada (LCA), Campus Miguelete, San Martín 1650, Buenos Aires, Argentina;
4 Max Planck Institute for Polymer Research, Department of Physical Chemistry of Polymers, Ackermannweg 10, 55128 Mainz, Germany;