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한국과학기술연구원, UST

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Nat. Commun., Published: 30 May 2025 | https://doi.org/10.1038/s41467-025-60380-6 Premixing enables loading of long RNA in cubic phase lipid nanoparticles

Harin Jin^1,2,9, Iji Seo^2,3,9, Jongeon Park^2,4,9, Yunhee Seo⁵, Jae Chul Park², Seunghwan Bang^1,2, Joonwoo Rhee², Kwan Hyi Lee^2,6, Jahyun Koo⁴, Youngdo Jeong^2,7, Ji-Hoon Kim^2,8 & Hojun Kim^1,2

¹Division of Bio-Medical Science and Technology, KIST school, University of Science and Technology (UST), Seoul, Republic of Korea.
²Center for Advanced Biomolecular Recognition, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea.
³Department of Cancer Biology, Seoul National University Cancer Research Institute, Seoul, Republic of Korea.
⁴School of Biomedical Engineering, Korea University, Seoul, Republic of Korea.
⁵Advanced Analysis and Data Center, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea.
⁶KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, Republic of Korea.
⁷Department of HY-KIST Bio-convergence, Hanyang University, Seoul, Republic of Korea.
⁸Department of KHU-KIST Convergence Science and Technology, Kyung Hee University, Seoul, Republic of Korea.
⁹These authors contributed equally: Harin Jin, Iji Seo, Jongeon Park.

Corresponding authors
Correspondence to Ji-Hoon Kim or Hojun Kim.

Abstract

Cubic phase lipid nanoparticles (cubosomes) show promise as carriers for nucleic acids due to their outstanding delivery performance and physical stability. However, both theoretical analysis and experimental results have shown that encapsulating long RNA is almost impossible while maintaining a cubic structure. Here we show successful encapsulation of long RNA (up to 4000 bases) in cubosomes by premixing RNA and lipids before self-assembly. Surprisingly, we discovered that long RNA within cubosomes folded into an isotropic phase, similar to other lipid self-assembly structures encapsulating nucleic acids. The cubosome–long RNA complex maintained excellent delivery efficiency even after 24 days at room temperature, underpinning its exceptional stability. Our premixing strategy not only demonstrates the feasibility of developing cold chain-free mRNA vaccines, but also offers insights for incorporating large cargo into other liquid crystals, such as peptides and/or polymer materials.

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