Cited by 236RNA Interference and Gene DeliveryNanoparticle-Based Drug DeliveryLipid Membrane Structure and Behavior

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Encapsulation state of messenger RNA inside lipid nanoparticles

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Brader, Mark L., Williams, Sean J., Banks, Jessica M., Hui, Wong H., Zhou, Z. Hong, Jin, Lin·2021·Biophysical Journal

DOI 10.1016/j.bpj.2021.03.012PMC PMC8390897

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Abstract

Understanding the structure of messenger RNA (mRNA) lipid nanoparticles, and specifically the microenvironment of the mRNA molecules within these entities, is fundamental to advancing their biomedical potential. Here, we show that a permeating cationic dye, thionine, can serve as a cryogenic electron microscopy contrasting agent by binding selectively to encapsulated mRNA without disturbing lipid nanoparticle morphology. Cryo-electron microscopy images identify the mRNA location, revealing that mRNA may exist within solvent-filled cavities or may be substantially lipid associated.

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Figure 1 Characterization of dye-binding and permeation. (a) Isothermal titration calorimetry of thionine titrated into mRNA. (Top) Raw data. (Bottom) Integrated heats of each injection versus molar ratio of thionine/nucleotide together with a fit using a one-site binding model. (b) Optical signatures of the thionine-mRNA binding interaction. Visible absorption spectra (top) of thionine at 0.0255 mM recorded in the absence of mRNA and in the presence of mRNA at low (4) and high (160) nucleotide/dye molar ratios (P/D). Corresponding circular dichroism (CD) spectra (bottom) show that at low P/D, the thionine absorption bands are resolved into negative and positive CD bands with extrema at 565 and 628 nm, respectively, whereas at high P/D, the induced CD is weak and characterized by a single positive band at 632 nm. (c) Dye permeation kinetics corresponding to mRNA-LNP added to a thionine solution. (Left) Scanning kinetics showing the spectral change as a function of time with scans taken at 2-min intervals. (Right) Kinetic time course of 600 nm absorbance together with a fit (red) to a first-order process with a rate constant of k = 0.143 min−1. (d) Nanoparticle tracking analysis of mRNA-LNP in the presence and absence of 0.5 mM thionine, showing small or insignificant effects of thionine on particle size and charge. Data represent the mean and error of 3 independent samples. (Left) Size distribution. (Right) ζ potential distribution.CC BY · PubMed Central

Figure 2 Visualizing free mRNA. Images show contrast enhancement using thionine of a 4000 nucleotide mRNA molecule. In the absence of dye (left), the resolution is comparable to published examples (25), whereas in the presence of 0.1 mM thionine (right), extended strand and molecular branching is more clearly discernible.CC BY · PubMed Central

Figure 3 Locating encapsulated mRNA in LNPs by cryo-EM. The effect of thionine on mRNA-LNPs of different morphologies reveals that lipid-dissociated mRNA may reside in bleb compartments (a) or may be more lipid-associated in spherical (b) or less prominently blebbed particles (c). The black arrow in (a) indicates the distinctive mottled mass density of mRNA inside the bleb cavity, which itself is distinguished by a thick, dark periphery. The blue arrow indicates the significant contrast enhancement that occurs when thionine dye is present, thereby identifying mRNA within the bleb. (d) Charge-driven migration of mRNA from the bleb into the body of the LNP. When the mRNA-LNP sample of (a) (no dye) was dialyzed into pH 5 buffer, the images of (d) resulted. The mottled density is now associated with the body of the LNP (green arrow), leaving the bleb cavity devoid of mRNA (white arrow). Addition of thionine to this sample produced no notable contrast change (right), indicating that thionine did not displace lipid.CC BY · PubMed Central

Figure 4 LNP physical degradation pathways. (a) Effects of physical stress on the LNP highlighted by dye. A dye-stained mRNA-LNP sample was subjected to multiple freeze-thaws. The resulting effects of this physical stress are evident, revealing aggregation (right), liberated mRNA (blue arrow), and the formation of liposomal structures containing mRNA (red arrow). The black arrow indicates an LNP that appears ready to burst. This image appears to capture a snapshot of how physical degradation leads to loss of mRNA encapsulation. (b) NTA size distribution profiles corresponding to the stressed and unstressed sample. Mean values with error bars are plotted. A cryo-EM image of the original unstressed LNP sample is provided as Data S2.CC BY · PubMed Central

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“9,12 Lipid-RNA organization may thus serve as a fundamental “fingerprint” property that governs LNP characteristics and intracellular dynamics.”
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Liao, S., Wang, S., Wadhwa, A., Birkenshaw, A., Fox, K., Cheng, M. H. Y., Casmil, I. C., Magaña, A. A., Bathula, N. V., Ho, C.-H., et al. (2024) · ACS Applied Materials & Interfaces · doi:10.1021/acsami.4c20077 · Cited by 47
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Evaluating how cationic lipid affects mRNA-LNP physical properties and biodistribution
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Rational design of lipid nanoparticles for enabling gene therapies
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“184 Both situations appear to drive the ionizable lipid that is not associated with nucleic acid cargo into separate domains at pH 4, leading to more complete separation of mRNA cargo from ioniz-able cationic lipid and improved mRNA stability.”
Why mRNA-ionizable LNPs formulations are so short-lived: causes and way-out
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Lipid Nanoparticle-Enabled Intracellular Delivery of Prime Editors
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Background
Microfluidic ultrasonic cavitation enables versatile and scalable synthesis of monodisperse nanoparticles for biomedical application
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Single-Particle Spectroscopic Chromatography Reveals Heterogeneous RNA Loading and Size Correlations in Lipid Nanoparticles
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“…cannot be provided by the mainstream analysis methods such as dynamic light scattering (DLS), 27 cryogenic transmission electron microscopy (cryo-TEM), 25,28,29 nuclear magnetic resonance (NMR), 30 analytical ultracentrifugation, 31,32 and small-angle X-ray and neutron scattering (SAXS and SANS).”
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Background
Analytical Characterization of Heterogeneities in mRNA-Lipid Nanoparticles Using Sucrose Density Gradient Ultracentrifugation
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Brief Comparison of the Efficacy of Cationic and Anionic Liposomes as Nonviral Delivery Systems
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Elucidating lipid nanoparticle properties and structure through biophysical analyses
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Preformed Vesicle Approach to LNP Manufacturing Enhances Retinal mRNA Delivery
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“Such micellar, or even “bleb,” structures at the LNP surface align with previous experimental observations ( 52 ) and are associated with high local concentrations of ionizable lipid ( 49 ).”
Computational Methods for Modeling Lipid-Mediated Active Pharmaceutical Ingredient Delivery
Paloncýová, M., Valério, M., dos Santos, R. N., Kührová, P., Šrejber, M., Čechová, P., Dobchev, D. A., Balsubramani, A., Banáš, P., Agarwal, V., et al. (2025) · Molecular Pharmaceutics · doi:10.1021/acs.molpharmaceut.4c00744 · Cited by 35
mRNA Synthesis and Encapsulation in Ionizable Lipid Nanoparticles
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The influence of citrate buffer molarity on mRNA-LNPs: Exploring factors beyond general critical quality attributes
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Lipid Vesicles and Other Polymolecular Aggregates—From Basic Studies of Polar Lipids to Innovative Applications
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Angle-dependent effects in DLS measurements of polydisperse particles
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“mRNA LNP drug products were produced atModerna (Cambridge,MA) as described previously [20].”
Method
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Messerian, K. O., Зверев, А. И., Kramarczyk, J. F., & Zydney, A. L. (2022) · Biotechnology and Bioengineering · doi:10.1002/bit.28200 · Cited by 28
“All experiments were performed with LNPs whose properties were consistent with those described by Hassett et al. (2021) and Brader et al. (2021).”
BackgroundMethodInfluential
Membrane technology for the purification of RNA and DNA therapeutics
Javidanbardan, A., Messerian, K. O., & Zydney, A. L. (2024) · Trends in biotechnology · doi:10.1016/j.tibtech.2023.11.016 · Cited by 30
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Martini 3 Building Blocks for Lipid Nanoparticle Design
Kjølbye, L. R., Valério, M., Paloncýová, M., Borges-Araújo, L., Pestana-Nobles, R., Grünewald, F., Bruininks, B. M. H., Araya‐Osorio, R., Šrejber, M., Mera‐Adasme, R., et al. (2025) · Journal of Chemical Theory and Computation · doi:10.1021/acs.jctc.5c01207 · Cited by 28
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Loading of Extracellular Vesicles with Nucleic Acids via Hybridization with Non‐Lamellar Liquid Crystalline Lipid Nanoparticles
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The Novelty of mRNA Viral Vaccines and Potential Harms: A Scoping Review
Halma, M. T. J., Rose, J., Jenks, A., & Lawrie, T. A. (2023) · J — Multidisciplinary Scientific Journal · doi:10.3390/j6020017 · Cited by 25
Mesoscopic Structure of Lipid Nanoparticle Formulations for mRNA Drug Delivery: Comirnaty and Drug-Free Dispersions
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Understanding structure activity relationships of Good HEPES lipids for lipid nanoparticle mRNA vaccine applications
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Atomic Force Microscopic Imaging of mRNA-lipid Nanoparticles in Aqueous Medium
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Coarse-Grained Simulation of mRNA-Loaded Lipid Nanoparticle Self-Assembly
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On the Influence of Nucleic Acid Backbone Modifications on Lipid Nanoparticle Morphology
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Ionizable Drugs Enable Intracellular Delivery of Co‐Formulated siRNA
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Mechanistic modeling of lipid nanoparticle formation for the delivery of nucleic acid therapeutics
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Authors: Brader, M. L., Williams, S. J., Banks, J. M., Hui, W. H., Zhou, Z. H., & Jin, L.
Affiliations: California NanoSystems Institute (US)
Corresponding author: Brader, Mark L.
ORCID: Brader, Mark L.
Williams, Sean J.
Zhou, Z. Hong
Jin, Lin
Venue: Biophysical Journal
Publisher: Elsevier BV
Published: 2021-07
Volume: 120
Issue: 14
Pages: 2766-2770
ISSN: 0006-3495 (ISSN-L)
DOI: 10.1016/j.bpj.2021.03.012
PMC: PMC8390897
OpenAlex: W3139111210
Cited by: 236
References: 27
Citations by year: 2026: 40 · 2025: 59 · 2024: 58 · 2023: 40 · 2022: 27 · 2021: 12
FWCI: 10.75
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
creativecommons.org/licenses/by/4.0/ (vor)
Locations: Biophysical Journal (publishedVersion, cc-by)
Europe PMC (PubMed Central) (publishedVersion, other-oa)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
eScholarship (California Digital Library) (submittedVersion)
eScholarship (California Digital Library) (submittedVersion, cc-by)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
Keywords: mRNA lipid nanoparticles, mRNA encapsulation, thionine, mRNA localization
MeSH terms: Lipids, RNA, Messenger, Cryoelectron Microscopy, Nanoparticles

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Encapsulation state of messenger RNA inside lipid nanoparticles

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