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

Gilbert, Jennifer LU orcid ; Sebastiani, Federica LU ; Arteta, Marianna Yanez ; Terry, Ann LU ; Fornell, Anna LU ; Russell, Robert ; Mahmoudi, Najet and Nylander, Tommy LU (2024) In Journal of Colloid and Interface Science 660. p.66-76
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)... (More)

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<polyA<DNA, following the expected extent of base-pairing.

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author
; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Colloid and Interface Science
volume
660
pages
11 pages
publisher
Elsevier
external identifiers
  • pmid:38241872
  • scopus:85182743795
ISSN
0021-9797
DOI
10.1016/j.jcis.2023.12.165
language
English
LU publication?
yes
id
156111b2-6bef-4c7d-bb04-137418227fea
date added to LUP
2024-02-16 14:26:19
date last changed
2024-04-17 08:50:37
@article{156111b2-6bef-4c7d-bb04-137418227fea,
  abstract     = {{<p>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&lt;polyA&lt;DNA, following the expected extent of base-pairing.</p>}},
  author       = {{Gilbert, Jennifer and Sebastiani, Federica and Arteta, Marianna Yanez and Terry, Ann and Fornell, Anna and Russell, Robert and Mahmoudi, Najet and Nylander, Tommy}},
  issn         = {{0021-9797}},
  language     = {{eng}},
  month        = {{04}},
  pages        = {{66--76}},
  publisher    = {{Elsevier}},
  series       = {{Journal of Colloid and Interface Science}},
  title        = {{Evolution of the structure of lipid nanoparticles for nucleic acid delivery : From in situ studies of formulation to colloidal stability}},
  url          = {{http://dx.doi.org/10.1016/j.jcis.2023.12.165}},
  doi          = {{10.1016/j.jcis.2023.12.165}},
  volume       = {{660}},
  year         = {{2024}},
}