Evolution of the structure of lipid nanoparticles for nucleic acid delivery: from in situ studies of formulation to colloidal stability

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dc.contributor.authorGilbert, Jen_AU
dc.contributor.authorSebastiani, Fen_AU
dc.contributor.authorYanez Arteta, Men_AU
dc.contributor.authorTerry, Aen_AU
dc.contributor.authorFornell, Aen_AU
dc.contributor.authorRussell, RAen_AU
dc.contributor.authorMahmoudi, Nen_AU
dc.contributor.authorNylander, Ten_AU
dc.date.accessioned2024-02-28T00:31:18Zen_AU
dc.date.available2024-02-28T00:31:18Zen_AU
dc.date.issued2024-04-15en_AU
dc.date.statistics2024-02-27en_AU
dc.description.abstractThe development of lipid nanoparticle (LNP) based therapeutics for delivery of RNA has triggered the advance of new strategies for formulation, such as high throughput microfluidics for precise mixing of components into well-defined particles. In this study, we have characterised the structure of LNPs throughout the formulation process using in situ small angle x-ray scattering in the microfluidic chip, then by sampling in the subsequent dialysis process. The final formulation was investigated with small angle x-ray (SAXS) and neutron (SANS) scattering, dynamic light scattering (DLS) and cryo-TEM. The effect on structure was investigated for LNPs with a benchmark lipid composition and containing different cargos: calf thymus DNA (DNA) and two model mRNAs, polyadenylic acid (polyA) and polyuridylic acid (polyU). The LNP structure evolved during mixing in the microfluidic channel, however was only fully developed during the dialysis. The colloidal stability of the final formulation was affected by the type of incorporated nucleic acids (NAs) and decreased with the degree of base-pairing, as polyU induced extensive particle aggregation. The main NA LNP peak in the SAXS data for the final formulation were similar, with the repeat distance increasing from polyU<polyA<DNA, following the expected extent of base-pairing. © 2023 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license.en_AU
dc.description.sponsorshipThis work benefited from the use of the SasView application, originally developed under National Science Foundation, NSF, award DMR-0520547. SasView contains code developed with funding from the European Union's Horizon 2020 research and innovation programme under the SINE2020 project, grant agreement No 654000. The deuterated cholesterol used in this work was provided by the National Deuteration Facility, which is partly funded by the National Collaborative Research Infrastructure Strategy (NCRIS) – an Australian Government initiative. Research conducted at MAX IV, a Swedish national user facility, was supported by the Swedish Research Council under contract 2018-07152, the Swedish Governmental Agency for Innovation Systems under contract 2018-04969, and Formas under contract 2019-02496. We acknowledge the use of the “AdaptoCell for MAX IV Laboratory users” platform developed under the Swedish Foundation for Strategic Research, grant ITM-0375. The financial support from Swedish Research Council under contract 2017-06716 and 2020-05421 and from NanoLund is gratefully acknowledged. We thank the ISIS Neutron and Muon source (UK) for allocating beamtime on Sans2d (RB1920532). We also would like to acknowledge Professor Joachim Rädler for inspirational discussion.en_AU
dc.identifier.citationGilbert, J., Sebastiani, F., Yanez Arteta, M., Terry, A., Fornell, A., Russell, R., Mahmoudi, N., & Nylander, T. (2024). Evolution of the structure of lipid nanoparticles for nucleic acid delivery: from in situ studies of formulation to colloidal stability. Journal of Colloid and Interface Science, 660, 66-76. doi:10.1016/j.jcis.2023.12.165en_AU
dc.identifier.issn0021-9797en_AU
dc.identifier.journaltitleJournal of Colloid and Interface Scienceen_AU
dc.identifier.pagination66-76en_AU
dc.identifier.urihttps://apo.ansto.gov.au/handle/10238/15462en_AU
dc.identifier.volume660en_AU
dc.language.isoenen_AU
dc.publisherElsevieren_AU
dc.relation.urihttps://doi.org/10.1016/j.jcis.2023.12.165en_AU
dc.subjectLipidsen_AU
dc.subjectNanoparticlesen_AU
dc.subjectNucleic acidsen_AU
dc.subjectColloidsen_AU
dc.subjectStabilityen_AU
dc.subjectTherapeutic usesen_AU
dc.subjectRNAen_AU
dc.subjectSmall angle scatteringen_AU
dc.subjectNeutron diffractionen_AU
dc.subjectTransmission electron microscopyen_AU
dc.titleEvolution of the structure of lipid nanoparticles for nucleic acid delivery: from in situ studies of formulation to colloidal stabilityen_AU
dc.typeJournal Articleen_AU
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