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정상용Sangyong Jung

차의과학대학교

ACS Nano, Apr 19 2024, | https://doi.org/10.1021/acsnano.4c00587 Elucidating Structural Configuration of Lipid Assemblies for mRNA Delivery Systems

Hyunhyuk Tae ¹, Soohyun Park ¹, Li Yang Tan ^2,3, Chungmo Yang ¹, Yong-An Lee ⁴, Younghwan Choe ¹, Torsten Wüstefeld ^5,4,6, Sangyong Jung^2,7, Nam-Joon Cho¹

¹School of Materials Science and Engineering, Nanyang Technological University, 50 Nanyang Avenue, Singapore 639798, Singapore.

²Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore 138673, Singapore.

³Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore.

⁴Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), 60 Biopolis Street, Singapore 138672, Singapore.

⁵Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 637551, Singapore.

⁶School of Biological Science, Nanyang Technological University, Singapore 637551, Singapore.

⁷Department of Medical Science, College of Medicine, CHA University, Seongnam 13488, Republic of Korea.

H.T.and S.P. contributed equally to this work.

Corresponding Authors : Sangyong Jung, Nam-Joon Cho

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.

논문정보

형식Research article
게재일2024년 04월 (BRIC 등록일 2024-04-22)
연구진국내(교신)+국외 연구진
분야 바이오·의료융합 > 바이오센싱 및 나노바이오물질

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