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Purpose: This study aimed to test the feasibility of using Small Angle X-ray Scattering (SAXS) coupled with Density from Solution Scattering (DENSS) algorithm to characterize the internal architecture of messenger RNA-containing lipid nanoparticles (mRNA-LNPs).
Methods: The DENSS algorithm was employed to construct a three-dimensional model of average individual mRNA-LNP. The reconstructed models were cross validated with cryogenic transmission electron microscopy (cryo-TEM), and dynamic light scattering (DLS) to assess size, morphology, and internal structure.
Results: Cryo-TEM and DLS complemented SAXS, revealed a core-shell mRNA-LNP structure with electron-rich mRNA-rich region at the core, surrounded by lipids. The reconstructed model, utilizing the DENSS algorithm, effectively distinguishes mRNA and lipids via electron density mapping. Notably, DENSS accurately models the morphology of the mRNA-LNPs as an ellipsoidal shape with a "bleb" architecture or a two-compartment structure with contrasting electron densities, corresponding to mRNA-filled and empty lipid compartments, respectively. Finally, subtle changes in the LNP structure after three freeze-thaw cycles were detected by SAXS, demonstrating an increase in radius of gyration (Rg) associated with mRNA leakage.
Conclusion: Analyzing SAXS profiles based on DENSS algorithm to yield a reconstructed electron density based three-dimensional model can be a useful physicochemical characterization method in the toolbox to study mRNA-LNPs and facilitate their development.
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http://dx.doi.org/10.1007/s11095-024-03671-9 | DOI Listing |
Pharm Res
March 2024
Division of Molecular Pharmaceutics and Drug Delivery, College of Pharmacy, The University of Texas at Austin, Austin, TX, 78712, USA.
Purpose: This study aimed to test the feasibility of using Small Angle X-ray Scattering (SAXS) coupled with Density from Solution Scattering (DENSS) algorithm to characterize the internal architecture of messenger RNA-containing lipid nanoparticles (mRNA-LNPs).
Methods: The DENSS algorithm was employed to construct a three-dimensional model of average individual mRNA-LNP. The reconstructed models were cross validated with cryogenic transmission electron microscopy (cryo-TEM), and dynamic light scattering (DLS) to assess size, morphology, and internal structure.
J Appl Crystallogr
February 2024
The Biophysics Collaborative Access Team (BioCAT), Department of Physics, Illinois Institute of Technology, Chicago, IL 60616, USA.
is a free open-source program for reduction, analysis and modelling of biological small-angle scattering data. Here, the new developments in version 2 are described. These include improved data reduction using ; updated automated Guinier fitting and finding algorithms; automated series ( size-exclusion chromatography coupled small-angle X-ray scattering or SEC-SAXS) buffer- and sample-region finding algorithms; linear and integral baseline correction for series; deconvolution of series data using regularized alternating least squares (); creation of electron-density reconstructions using electron density via solution scattering (); a comparison window showing residuals, ratios and statistical comparisons between profiles; and generation of PDF reports with summary plots and tables for all analysis.
View Article and Find Full Text PDFBiophys J
December 2023
Department of Structural Biology, Jacobs School of Medicine and Biomedical Sciences, SUNY University at Buffalo, Buffalo, New York. Electronic address:
Solution scattering techniques, such as small- and wide-angle X-ray scattering (SWAXS), provide valuable insights into the structure and dynamics of biological macromolecules in solution. In this study, we present an approach to accurately predict solution X-ray scattering profiles at wide angles from atomic models by generating high-resolution electron density maps. Our method accounts for the excluded volume of bulk solvent by calculating unique adjusted atomic volumes directly from the atomic coordinates.
View Article and Find Full Text PDFbioRxiv
December 2023
The Biophysics Collaborative Access Team (BioCAT), Department of Physics, Illinois Institute of Technology, Chicago, IL 60616, USA.
BioXTAS RAW is a free, open-source program for reduction, analysis and modelling of biological small angle scattering data. Here, the new developments in RAW version 2 are described. These include: improved data reduction using pyFAI; updated automated Guinier fitting and finding algorithms; automated series (e.
View Article and Find Full Text PDFbioRxiv
June 2023
Department of Structural Biology, Jacobs School of Medicine and Biomedical Sciences, SUNY University at Buffalo, Buffalo, NY, USA.
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