Monodisperse mRNA-Loaded Lipid Nanoparticles Enabled by Optimizing an Ionizable Cationic Lipid

  • Langmuir. 2026 Feb 3;42(4):3391-3399. doi: 10.1021/acs.langmuir.5c05504.
Yui Toyoda  1 ,  Yuuta Miyazaki  1 ,  Sachiko Tsuda  1 ,  Hiroki Yamamura  2 ,  Nanako Shimada  3 ,  Isamu Akiba  3
Affiliations
  • 1. JSR Bioscience and Informatics R&D Center, 25 Miyukigaoka, Tsukuba, Ibaraki 3050841, Japan.
  • 2. JSR Material Characterization and Analysis Laboratory, 100 Kawajiri-cho, Yokkaichi, Mie 5108552, Japan.
  • 3. Department of Chemistry and Biochemistry, The University of Kitakyushu, 1-1 Hibikino, Wakamatsu, Kitakyushu 8080135, Japan.
PMID: 41534094 DOI: 10.1021/acs.langmuir.5c05504
Abstract

Messenger RNA (mRNA)-loaded lipid nanoparticles (LNPs) represent a transformative platform for nucleic acid delivery. Among various ionizable Cationic Lipids, [7-[4-(dipropylamino)butyl]-7-hydroxy-13-[(Z)-octadec-9-enoyl]oxytridecyl] (Z)-octadec-9-enoate (CL4H6) has recently emerged as a promising alternative to DLin-MC3-DMA. In this study, we investigate the physicochemical properties and internal structures of mRNA-loaded CL4H6-LNPs using small-angle X-ray scattering (SAXS), dynamic light scattering (DLS), asymmetric flow field-flow fractionation coupled with multiangle light scattering and differential refractive index (AF4-MALS/dRI), and cryogenic transmission electron microscopy. SAXS and DLS analyses reveal that certain lipid compositions yield mRNA-loaded CL4H6-LNPs with remarkably narrow size distributions. The formation of monodisperse LNPs achieved even in a multicomponent system without optimized molecular design suggests that CL4H6 is structurally suited for forming the LNP with a specific curvature of the surface. The combined results of SAXS and AF4-MALS/dRI indicate that compositional control─particularly the CL4H6-to-DSPC and Cholesterol ratios─critically governs the uniformity of the internal structure and dispersity of mRNA-loaded CL4H6-LNPs.

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