open access publication

Article, 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, ISSN 0021-9797, 1095-7103, Volume 660, Pages 66-76, 10.1016/j.jcis.2023.12.165

Contributors

Gilbert, Jennifer 0000-0001-8951-710X [1] Sebastiani, Federica 0000-0002-7405-6125 [1] [2] Arteta, Marianna Yanez [3] Terry, Ann E [1] Fornell, Anna 0000-0001-7980-376X [1] Russell, Robert A 0000-0002-6819-8194 [4] Mahmoudi, Najet 0000-0003-4936-6911 [5] Nylander, Tommy 0000-0001-9420-2217 (Corresponding author) [1] [6] [7]

Affiliations

  1. [1] Lund University
    2. [NORA names: Sweden; Europe, EU; Nordic; OECD];
  2. [2] University of Copenhagen
    3. [NORA names: KU University of Copenhagen; University; Denmark; Europe, EU; Nordic; OECD];
  3. [3] AstraZeneca (Sweden)
    4. [NORA names: Sweden; Europe, EU; Nordic; OECD];
  4. [4] Australian Nuclear Science and Technology Organisation
    5. [NORA names: Australia; Oceania; OECD];
  5. [5] ISIS Neutron and Muon Source
    6. [NORA names: United Kingdom; Europe, Non-EU; OECD];

Abstract

The 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

Keywords

DNA, PolyU, RNA, SAXS, SAXS data, X-ray, X-ray scattering, acid, acid delivery, aggregation, angle X-ray scattering, base pairs, calf thymus DNA, calves, cargo, channel, chip, colloidal stability, components, composition, cryo-TEM, data, degree, degree of base pairing, delivery, delivery of RNA, development, development of lipid nanoparticles, dialysis, dialysis process, distance, dynamic light scattering, effect, evolution, extensive particle aggregation, formulation, formulation process, in situ small-angle X-ray scattering, in situ studies, light scattering, lipid, lipid composition, lipid nanoparticle structure, lipid nanoparticles, mRNA, microfluidic channel, microfluidic chip, microfluidics, mixing, model, model mRNAs, nanoparticles, neutron, nucleic acid delivery, nucleic acids, particle aggregation, particles, peak, polyA, polyadenylic acid, polyuridylic acid, process, repeat distance, repeats, samples, scattering, small-angle X-ray, small-angle X-ray scattering, stability, strategies, structure, structure of lipid nanoparticles, studies of formulations, study, therapeutics, thymus DNA

Funders

  • VINNOVA
  • Swedish Research Council
  • Swedish Research Council for Environment Agricultural Sciences and Spatial Planning
  • Directorate for Mathematical & Physical Sciences
  • Swedish Foundation for Strategic Research
  • European Commission
  • Science and Technology Facilities Council

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