Structure of lipid nanoparticles containing siRNA or mRNA by dynamic nuclear polarization-enhanced NMR spectroscopy

Viger-Gravel, Jasmine; Schantz, Anna; Pinon, Arthur C.; Rossini, Aaron J.; Schantz, Staffan; Emsley, Lyndon

doi:10.1021/acs.jpcb.7b10795

Cited by 202RNA Interference and Gene DeliveryNanoparticle-Based Drug DeliveryAdvanced NMR Techniques and Applications

Structure of lipid nanoparticles containing siRNA or mRNA by dynamic nuclear polarization-enhanced NMR spectroscopy

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Viger-Gravel, Jasmine, Schantz, Anna, Pinon, Arthur C., Rossini, Aaron J., Schantz, Staffan, Emsley, Lyndon·2018·The Journal of Physical Chemistry B

DOI 10.1021/acs.jpcb.7b10795

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Abstract

Here, we show how dynamic nuclear polarization (DNP) NMR spectroscopy experiments permit the atomic level structural characterization of loaded and empty lipid nanoparticles (LNPs). The LNPs used here were synthesized by the microfluidic mixing technique and are composed of ionizable cationic lipid (DLin-MC3-DMA), a phospholipid (distearoylphosphatidylcholine, DSPC), cholesterol, and poly(ethylene glycol) (PEG) (dimyristoyl phosphatidyl ethanolamine (DMPE)–PEG 2000), as well as encapsulated cargoes that are either phosphorothioated siRNA (50 or 100%) or mRNA. We show that LNPs form physically stable complexes with bioactive drug siRNA for a period of 94 days. Relayed DNP experiments are performed to study 1 H– 1 H spin diffusion and to determine the spatial location of the various components of the LNP by studying the average enhancement factors as a function of polarization time. We observe a striking feature of LNPs in the presence and in the absence of encapsulating siRNA or mRNA by comparing our experimental results to numerical spin-diffusion modeling. We observe that LNPs form a layered structure, and we detect that DSPC and DMPE–PEG 2000 lipids form a surface rich layer in the presence (or absence) of the cargoes and that the cholesterol and ionizable cationic lipid are embedded in the core. Furthermore, relayed DNP 31 P solid-state NMR experiments allow the location of the cargo encapsulated in the LNPs to be determined. On the basis of the results, we propose a new structural model for the LNPs that features a homogeneous core with a tendency for layering of DSPC and DMPE–PEG at the surface.

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There are indications that mRNA is located in the core of the LNPs and siRNA more towards the surface and mRNA can form 'blebs'.
“Besides, there are indications that mRNA is located in the core of the LNPs and siRNA more towards the surface and mRNA can form ‘blebs’ (Fig. 2) (Viger-Gravel et al., 2018).”
From mRNA-lipid nanoparticle COVID-19 vaccines: structure and stability (2021) · cites this paper as Viger-Gravel et al., 2018
For siRNA only weak electrostatic interactions were found with the ionizable cationic lipid, indicating that at least for siRNA-LNP formulations the pH inside approaches or equals the pH outside.
“For siRNA only weak electrostatic interactions were found with the ionizable cationic lipid, indicating that at least for siRNA-LNP formulations the pH inside approaches or equals the pH outside (Viger-Gravel et al., 2018).”
From mRNA-lipid nanoparticle COVID-19 vaccines: structure and stability (2021) · cites this paper as Viger-Gravel et al., 2018

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Lipid Nanoparticles Containing siRNA Synthesized by Microfluidic Mixing Exhibit an Electron-Dense Nanostructured Core
(2016)

Authors: Viger-Gravel, J., Schantz, A., Pinon, A. C., Rossini, A. J., Schantz, S., & Emsley, L.
Affiliations: Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland
Iowa State University (US)
École Polytechnique Fédérale de Lausanne (CH)
AstraZeneca (Sweden) (SE)
Corresponding author: Emsley, Lyndon
ORCID: Rossini, Aaron J.
Schantz, Staffan
Emsley, Lyndon
Venue: The Journal of Physical Chemistry B
Publisher: American Chemical Society (ACS)
Published: 2018-02-09
Volume: 122
Issue: 7
Pages: 2073-2081
ISSN: 1520-5207 (ISSN-L)
1520-6106
DOI: 10.1021/acs.jpcb.7b10795
OpenAlex: W2784187371
Cited by: 202
References: 50
Citations by year: 2026: 11 · 2025: 39 · 2024: 31 · 2023: 26 · 2022: 37 · 2021: 30 · 2020: 10 · 2019: 15 · 2018: 3
FWCI: 5.16
Type: journal article
Language: en
Open access: green
infoscience.epfl.ch
Licence: cc-by-nc-nd
Locations: The Journal of Physical Chemistry B (publishedVersion)
PubMed (publishedVersion)
Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
Funders: H2020 European Research Council (320860)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
Physical Sciences › Chemistry › Spectroscopy › Advanced NMR Techniques and Applications
Keywords: lipid nanoparticles, siRNA encapsulation, mRNA encapsulation, spin diffusion, 31P solid-state NMR, dynamic nuclear polarization, DSPC, cholesterol, ionizable cationic lipids, microfluidic mixing
MeSH terms: Dynamic Light Scattering, Phospholipids, RNA, Messenger, Molecular Structure, Nuclear Magnetic Resonance, Biomolecular, RNA, Small Interfering, Nanoparticles

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Structure of lipid nanoparticles containing siRNA or mRNA by dynamic nuclear polarization-enhanced NMR spectroscopy

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