Premixing enables loading of long RNA in cubic phase lipid nanoparticles
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.
Authors
- Youngdo Jeong (ORCID: https://orcid.org/0000-0003-3514-9094)
- Seunghwan Bang (ORCID: https://orcid.org/0000-0001-9621-1280)
- Jongeon Park (ORCID: https://orcid.org/0000-0002-2893-584X)
- Kwan H. Lee (ORCID: https://orcid.org/0000-0002-7891-844X)
- Harin Jin (ORCID: https://orcid.org/0009-0007-4882-7129)
- Jahyun Koo (ORCID: https://orcid.org/0000-0003-1503-0731)
- Jae Chul Park (ORCID: https://orcid.org/0000-0002-1157-4275)
- Yongho Seo (ORCID: https://orcid.org/0000-0002-5695-5493)
- Ilwan Seo (ORCID: https://orcid.org/0000-0003-3680-8776)
- Ji-Hoon Kim (ORCID: https://orcid.org/0000-0002-9217-4483)
- Hojun Kim (ORCID: https://orcid.org/0000-0001-7974-1044)
- J. Y. Rhee
Institutions
- Cancer Research Institute (US)
- Korea University (KR)
- Kyung Hee University (KR)
- Hanyang University (KR)
- Korea Institute of Science and Technology (KR)
- Korea University of Science and Technology (KR)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-05-30
- DOI
- https://doi.org/10.1038/s41467-025-60380-6
- Citations
- 3
- Primary Topic
- RNA Interference and Gene Delivery
- Type
- article
- Field-Weighted Citation Impact
- 2.42
Funders
- National Research Foundation
- Ministry of Agriculture, Food and Rural Affairs
- Korea Institute of Planning and Evaluation for Technology in Food, Agriculture, Forestry and Fisheries
- Korea Institute of Science and Technology
- Korea Health Industry Development Institute
- National Research Foundation of Korea
- Ministry of Science and ICT, South Korea
- Korea Institute of Planning and Evaluation for Technology in Food, Agriculture and Forestry