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Abstract
Efficient cytosolic delivery of RNA molecules remains a formidable barrier for RNA therapeutic strategies. Lipid nanoparticles (LNPs) serve as state-of-the-art carriers that can deliver RNA molecules intracellularly, as exemplified by the recent implementation of several vaccines against SARS-CoV-2. Using a bottom-up rational design approach, we assemble LNPs that contain programmable lipid phases encapsulating small interfering RNA (siRNA). A combination of cryogenic transmission electron microscopy, cryogenic electron tomography and small-angle X-ray scattering reveals that we can form inverse hexagonal structures, which are present in a liquid crystalline nature within the LNP core. Comparison with lamellar LNPs reveals that the presence of inverse hexagonal phases enhances the intracellular silencing efficiency over lamellar structures. We then demonstrate that lamellar LNPs exhibit an in situ transition from a lamellar to inverse hexagonal phase upon interaction with anionic membranes, whereas LNPs containing pre-programmed liquid crystalline hexagonal phases bypass this transition for a more efficient one-step delivery mechanism, explaining the increased silencing effect. This rational design of LNPs with defined lipid structures aids in the understanding of the nano-bio interface and adds substantial value for LNP design, optimization and use.
The authors display the bottom-up design, assembly, and in-depth characterization of defined lipid-RNA structures in the core of lipid nanoparticles. The inverted structures are thermostable and provide better transfection over lamellar structures.
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1 Leiden University, Einsteinweg 55, Supramolecular and Biomaterials Chemistry, Leiden Institute of Chemistry, Leiden, The Netherlands (GRID:grid.5132.5) (ISNI:0000 0001 2312 1970); Leiden University Medical Center, Einthovenweg 20, Department of Cell and Chemical Biology, Leiden, The Netherlands (GRID:grid.10419.3d) (ISNI:0000 0000 8945 2978); BioNTech SE, An der Goldgrube 12, Mainz, Germany (GRID:grid.434484.b) (ISNI:0000 0004 4692 2203)
2 Leiden University, Einsteinweg 55, Supramolecular and Biomaterials Chemistry, Leiden Institute of Chemistry, Leiden, The Netherlands (GRID:grid.5132.5) (ISNI:0000 0001 2312 1970)
3 Eindhoven University of Technology, P.O. Box 513, Self-Organizing Soft Matter, Department of Chemical Engineering and Chemistry & Institute of Complex Molecular Systems, Eindhoven, The Netherlands (GRID:grid.6852.9) (ISNI:0000 0004 0398 8763)
4 Leiden University Medical Center, Einthovenweg 20, Department of Cell and Chemical Biology, Leiden, The Netherlands (GRID:grid.10419.3d) (ISNI:0000 0000 8945 2978); University of Bristol, School of Biochemistry, Bristol, United Kingdom (GRID:grid.5337.2) (ISNI:0000 0004 1936 7603)