Work

Premixing enables loading of long RNA in cubic phase lipid nanoparticles

Year: 2025

Type: article

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. Cubosomes, cubic-phase lipid nanoparticles, are of interest for delivery application but have failed in the delivery of long RNA. Here, the authors report on a premixing strategy which allows for the loading of long RNA into cubosomes with the advantage of consistent delivery after room temperature storage.

Source: Nature Communications

DOI: 10.1038/s41467-025-60380-6