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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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