Please use this identifier to cite or link to this item: https://hdl.handle.net/10356/179414
Title: Elucidating structural configuration of lipid assemblies for mRNA delivery systems
Authors: Tae, Hyunhyuk
Park, Soohyun
Tan, Li Yang
Yang, Chungmo
Lee, Yong-An
Choe, Younghwan
Wüstefeld, Torsten
Jung, Sangyong
Cho, Nam-Joon
Keywords: Medicine, Health and Life Sciences
Issue Date: 2024
Source: Tae, H., Park, S., Tan, L. Y., Yang, C., Lee, Y., Choe, Y., Wüstefeld, T., Jung, S. & Cho, N. (2024). Elucidating structural configuration of lipid assemblies for mRNA delivery systems. ACS Nano, 18(17), 11284-11299. https://dx.doi.org/10.1021/acsnano.4c00587
Project: RG111/20 
RG34/22 
MOE-MOET32022-0002 
REQ414940
RCA-LUCA AICell REQ0239282
Journal: ACS Nano
Abstract: The development of mRNA delivery systems utilizing lipid-based assemblies holds immense potential for precise control of gene expression and targeted therapeutic interventions. Despite advancements in lipid-based gene delivery systems, a critical knowledge gap remains in understanding how the biophysical characteristics of lipid assemblies and mRNA complexes influence these systems. Herein, we investigate the biophysical properties of cationic liposomes and their role in shaping mRNA lipoplexes by comparing various fabrication methods. Notably, an innovative fabrication technique called the liposome under cryo-assembly (LUCA) cycle, involving a precisely controlled freeze-thaw-vortex process, produces distinctive onion-like concentric multilamellar structures in cationic DOTAP/DOPE liposomes, in contrast to a conventional extrusion method that yields unilamellar liposomes. The inclusion of short-chain DHPC lipids further modulates the structure of cationic liposomes, transforming them from multilamellar to unilamellar structures during the LUCA cycle. Furthermore, the biophysical and biological evaluations of mRNA lipoplexes unveil that the optimal N/P charge ratio in the lipoplex can vary depending on the structure of initial cationic liposomes. Cryo-EM structural analysis demonstrates that multilamellar cationic liposomes induce two distinct interlamellar spacings in cationic lipoplexes, emphasizing the significant impact of the liposome structures on the final structure of mRNA lipoplexes. Taken together, our results provide an intriguing insight into the relationship between lipid assembly structures and the biophysical characteristics of the resulting lipoplexes. These relationships may open the door for advancing lipid-based mRNA delivery systems through more streamlined manufacturing processes.
URI: https://hdl.handle.net/10356/179414
ISSN: 1936-0851
DOI: 10.1021/acsnano.4c00587
Schools: Lee Kong Chian School of Medicine (LKCMedicine) 
School of Biological Sciences 
School of Materials Science and Engineering 
Organisations: Genome Institute of Singapore, A*STAR
Rights: © 2024 American Chemical Society. All rights reserved.
Fulltext Permission: none
Fulltext Availability: No Fulltext
Appears in Collections:LKCMedicine Journal Articles

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