2. Academic Validation
  3. Mesoscopic Structure of Lipid Nanoparticle Formulations for mRNA Drug Delivery: Comirnaty and Drug-Free Dispersions

Mesoscopic Structure of Lipid Nanoparticle Formulations for mRNA Drug Delivery: Comirnaty and Drug-Free Dispersions

  • ACS Nano. 2024 Mar 21. doi: 10.1021/acsnano.4c02610.
Tobias Unruh 1 2,  Klaus Götz 1 2,  Carola Vogel 1 2,  Erik Fröhlich 1,  Andreas Scheurer 3,  Lionel Porcar 4,  Frank Steiniger 5
Affiliations

Affiliations

  • 1 Institute for Crystallography and Structural Physics, Physics Department, Friedrich-Alexander-Universität Erlangen-Nürnberg, Staudtstraße 3, 91058 Erlangen, Germany.
  • 2 Interdisciplinary Center for Nanostructured Films (IZNF) and Center for Nanoanalysis and Electron Microscopy (CENEM), Cauerstraße 3, 91058 Erlangen, Germany.
  • 3 Lehrstuhl für Anorganische und Allgemeine Chemie, Department Chemie und Pharmazie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Egerlandstraße 1, 91058 Erlangen, Germany.
  • 4 Large Scale Structures Group, Institut Laue-Langevin, 71 Avenue des Martyrs, 38042 Grenoble Cedex 9, France.
  • 5 Electron Microscopy Center, Jena University Hospital, Friedrich Schiller University Jena, 07743 Jena, Germany.
PMID: 38514237 DOI: 10.1021/acsnano.4c02610
Abstract

Lipid nanoparticles (LNPs) produced by antisolvent precipitation (ASP) are used in formulations for mRNA drug delivery. The mesoscopic structure of such complex multicomponent and polydisperse nanoparticulate systems is most relevant for their drug delivery properties, medical efficiency, shelf life, and possible side effects. However, the knowledge on the structural details of such formulations is very limited. Essentially no such information is publicly available for pharmaceutical dispersions approved by numerous medicine agencies for the use in humans and loaded with mRNA encoding a mimic of the spike protein of the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) as, e.g., the Comirnaty formulation (BioNTech/Pfizer). Here, we present a simple preparation method to mimic the Comirnaty drug-free LNPs including a comparison of their structural properties with those of Comirnaty. Strong evidence for the liquid state of the LNPs in both systems is found in contrast to the designation of the LNPs as solid lipid nanoparticles by BioNTech. An exceptionally detailed and reliable structural model for the LNPs i.a. revealing their unexpected narrow size distribution will be presented based on a combined small-angle X-ray scattering and photon correlation spectroscopy (SAXS/PCS) evaluation method. The results from this experimental approach are supported by LIGHT microscopy, 1H NMR spectroscopy, Raman spectroscopy, cryogenic electron microscopy (cryoTEM), and simultaneous SAXS/SANS studies. The presented results do not provide direct insights on particle formation or dispersion stability but should contribute significantly to better understanding the LNP drug delivery process, enhancing their medical benefit, and reducing side effects.

Keywords

BNT162b2 Comirnaty; PCS); dynamic light scattering (DLS; lipid nanoparticles (LNPs); mRNA drug delivery; proton nuclear magnetic resonance spectroscopy (1H NMR); severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2); small-angle X-ray scattering (SAXS).

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