Encapsulation state of messenger RNA inside lipid nanoparticles
Open accessAbstract
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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A key aspect of LNPs is the presence of lipids in the core, although water is also present to some extent.
“A key aspect of LNPs and the characteristic that makes them different from liposomes (spherical vesicles with at least one lipid bilayer and an aqueous core) is the presence of lipids in the core, although data from several studies indicate that water is also present to some extent (Yanez Arteta et al., 2018, Kulkarni et al., 2018, Brader et al., 2021).”
From mRNA-lipid nanoparticle COVID-19 vaccines: structure and stability (2021) · cites this paper as Brader et al., 2021
If the LNP shells are permeable to protons, the pH would be similar to the rest of the formulation, around 7 to 8, meaning that most of the ionizable cationic lipids would be uncharged.
“If the LNP shells are permeable to protons –which is likely, as ionized dyes such as 2-(p-toluidino)-6-napthalene sulfonic acid (TNS) and thionine can enter the LNP core (Jayaraman et al., 2012, Brader et al., 2021) – the pH would be similar to the rest of the formulation, around 7 to 8, meaning that most of the ionizable cationic lipids would be uncharged.”
From mRNA-lipid nanoparticle COVID-19 vaccines: structure and stability (2021) · cites this paper as Brader et al., 2021
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Morphological Characterization of Self-Amplifying mRNA Lipid Nanoparticles
Thelen, J. L., Leite, W. C., Urban, V. S., O’Neill, H., Grishaev, A., Curtis, J. E., Krueger, S., & Castellanos, M. M. (2024) · ACS Nano · doi:10.1021/acsnano.3c08014 · Cited by 47 · see citing works
The dynamic process of mRNA delivery by lipid nanoparticles in vivo
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Lipid-siRNA Organization Modulates the Intracellular Dynamics of Lipid Nanoparticles
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“9,12 Lipid-RNA organization may thus serve as a fundamental “fingerprint” property that governs LNP characteristics and intracellular dynamics.”
Transfection Potency of Lipid Nanoparticles Containing mRNA Depends on Relative Loading Levels
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 44 · see citing works
Atomistic Insights into Organization of RNA-Loaded Lipid Nanoparticles
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Evaluating how cationic lipid affects mRNA-LNP physical properties and biodistribution
Guéguen, C., Chimol, T. B., Briand, M., Renaud, K., Seiler, M., Ziesel, M., Erbacher, P., & Hellal, M. (2023) · European Journal of Pharmaceutics and Biopharmaceutics · doi:10.1016/j.ejpb.2023.08.002 · Cited by 39 · see citing works
Wu, K., Xu, F., Dai, Y., Jin, S., Zheng, A., Zhang, N., & Xu, Y. (2024) · Journal of Controlled Release · doi:10.1016/j.jconrel.2024.11.007 · Cited by 38 · see citing works
Rational design of lipid nanoparticles for enabling gene therapies
Brimacombe, C. A., Kulkarni, J. A., Cheng, M. H. Y., An, K., Witzigmann, D., & Cullis, P. R. (2025) · Molecular Therapy — Methods & Clinical Development · doi:10.1016/j.omtm.2025.101518 · Cited by 39 · see citing works
“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
De, A., & Ko, Y. T. (2023) · Expert Opinion on Drug Delivery · doi:10.1080/17425247.2023.2162876 · Cited by 36 · see citing works
Lipid Nanoparticle-Enabled Intracellular Delivery of Prime Editors
Herrera‐Barrera, M., Gautam, M., Lokras, A. G., Vlasova, K. Y., Foged, C., & Sahay, G. (2023) · The AAPS Journal · doi:10.1208/s12248-023-00833-2 · Cited by 37 · see citing works
“5 kb in length, it is likely that only a single transcript can be loaded into the LNPs [39].”
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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).”
Hardianto, A., Muscifa, Z. S., Widayat, W., Yusuf, M., & Subroto, T. (2023) · Molecules · doi:10.3390/molecules28124836 · Cited by 34 · see citing works
“Encapsulating RNA into LNPs also prevents cleavage by RNase in the blood [3].”
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Vaccine process technology—A decade of progress
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Brief Comparison of the Efficacy of Cationic and Anionic Liposomes as Nonviral Delivery Systems
Ochoa-Sánchez, C., Rodríguez-León, E., Iñiguez-Palomares, R. A., & Rodríguez-Beas, C. (2024) · ACS Omega · doi:10.1021/acsomega.4c06714 · Cited by 34 · see citing works
Wu, W., Oliveira, L. T., Jain, A., Karpov, Y., Olsen, K., Wu, Y., & Panicker, R. K. G. (2025) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2025.125520 · Cited by 34 · see citing works
Elucidating lipid nanoparticle properties and structure through biophysical analyses
Padilla, M. S., Shepherd, S. J., Hanna, A. R., Kurnik, M., Zhang, X., Chen, M., Byrnes, J., Joseph, R. A., Yamagata, H. M., Ricciardi, A. S., et al. (2025) · Nature Biotechnology · doi:10.1038/s41587-025-02855-x · Cited by 38 · see citing works
Preformed Vesicle Approach to LNP Manufacturing Enhances Retinal mRNA Delivery
Eygeris, Y., Henderson, M. I., Curtis, A. G., Jozić, A., Stoddard, J., Reynaga, R., Chirco, K. R., Su, G., Neuringer, M., Lauer, A. K., et al. (2024) · Small · doi:10.1002/smll.202400815 · Cited by 34 · see citing works
Toward understanding lipid reorganization in RNA lipid nanoparticles in acidic environments
Garaizar, A., Díaz‐Oviedo, C. D., Zablowsky, N., Rissanen, S., Köbberling, J., Sun, J., Steiger, C., Steigemann, P., Mann, F. A., & Meier, K. (2024) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2404555121 · Cited by 34 · see citing works
“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 33 · see citing works
mRNA Synthesis and Encapsulation in Ionizable Lipid Nanoparticles
McKenzie, R. E., Minnell, J. J., Ganley, M., Painter, G. F., & Draper, S. L. (2023) · Current Protocols · doi:10.1002/cpz1.898 · Cited by 35 · see citing works
Impact of mixing and shaking on mRNA-LNP drug product quality characteristics
Matthessen, R., Pottelberge, R. V., Goffin, B., & Winter, G. (2024) · Scientific Reports · doi:10.1038/s41598-024-70680-4 · Cited by 32 · see citing works
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Angle-dependent effects in DLS measurements of polydisperse particles
Jin, L., Jarand, C. W., Brader, M. L., & Reed, W. F. (2021) · Measurement Science and Technology · doi:10.1088/1361-6501/ac42b2 · Cited by 29 · see citing works
“mRNA LNP drug products were produced atModerna (Cambridge,MA) as described previously [20].”
MethodPressure‐dependent fouling behavior during sterile filtration of mRNA‐containing lipid nanoparticles
Messerian, K. O., Зверев, А. И., Kramarczyk, J. F., & Zydney, A. L. (2022) · Biotechnology and Bioengineering · doi:10.1002/bit.28200 · Cited by 29 · see citing works
“All experiments were performed with LNPs whose properties were consistent with those described by Hassett et al. (2021) and Brader et al. (2021).”
BackgroundMethodInfluentialMembrane technology for the purification of RNA and DNA therapeutics
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Martini 3 Building Blocks for Lipid Nanoparticle Design
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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 · see citing works
Unruh, T., Götz, K., Vogel, C. S., Fröhlich, E., Scheurer, A., Porcar, L., & Steiniger, F. (2024) · ACS Nano · doi:10.1021/acsnano.4c02610 · Cited by 24 · see citing works
Goldman, R., Murthy, N. T. V., Trent, N., Balakrishnan, A., Chivukula, S. V., Danz, H., Tibbitts, T. J., Dias, A., Vargas, J., Cooper, D. L., et al. (2023) · Biomaterials · doi:10.1016/j.biomaterials.2023.122243 · Cited by 26 · see citing works
Innovative vaccine platforms against infectious diseases: Under the scope of the COVID-19 pandemic
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Atomic Force Microscopic Imaging of mRNA-lipid Nanoparticles in Aqueous Medium
Takechi‐Haraya, Y., Usui, A., Izutsu, K., & Abe, Y. (2022) · Journal of Pharmaceutical Sciences · doi:10.1016/j.xphs.2022.11.026 · Cited by 24 · see citing works
Coarse-Grained Simulation of mRNA-Loaded Lipid Nanoparticle Self-Assembly
Grzetic, D. J., Hamilton, N. B., & Shelley, J. C. (2024) · Molecular Pharmaceutics · doi:10.1021/acs.molpharmaceut.4c00216 · Cited by 22 · see citing works
Wang, R., Zhang, Y., Zhong, H., Zang, J., Wang, W., Cheng, H., Chen, Y., & Ouyang, D. (2024) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2024.125114 · Cited by 21 · see citing works
mRNA vaccines: immunogenicity and quality characteristics
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“Moderna’s cryo-EM studies have visually demonstrated changes in LNP particle size and morphology under physical stress, showing aggregation and mRNA leakage after freeze-thaw cycles [194].”
McCollum, C. R., Courtney, C. M., O’Connor, N. J., Aunins, T. R., Ding, Y., Jordan, T. X., Rogers, K. L., Brindley, S. M., Brown, J. M., Nagpal, P., et al. (2022) · ACS Biomaterials Science & Engineering · doi:10.1021/acsbiomaterials.2c00510 · Cited by 20 · see citing works
Microfluidic and Turbulent Mixing for mRNA LNP Vaccines
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“The cationic lipid/mRNA LNP core was also examined with the mRNA binding dye thionine to enhance the contrast of mRNA in cryo-EM images of mRNA LNP [77].”
Lipid nanoparticle steric stabilization roadmap
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On the Influence of Nucleic Acid Backbone Modifications on Lipid Nanoparticle Morphology
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Messerian, K. O., Zverev, A., Kramarczyk, J. F., & Zydney, A. L. (2023) · Journal of Membrane Science · doi:10.1016/j.memsci.2023.121896 · Cited by 17 · see citing works
Probing Molecular Packing of Lipid Nanoparticles from 31P Solution and Solid-State NMR
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Delehedde, C., Ciganek, I., Bernard, P.-L., Laroui, N., Silva, C. C. D., Gonçalves, C., Nunès, J. A., Griscelli, A. B., Imeri, J., Huyghe, M., et al. (2024) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2024.102263 · Cited by 17 · see citing works
“26,32,40 In contrast with LNPs, mRNA is sandwiched by lipid bilayers in Lx. Imidazolium Lx exposes positive charges on their surface, which likely favor the interaction with the cell plasma membrane.”
Ionizable Drugs Enable Intracellular Delivery of Co‐Formulated siRNA
Slaughter, K. V., Donders, E. N., Jones, M. S., Sabbah, S. G., Elliott, M. J., Shoichet, B. K., Cescon, D. W., & Shoichet, M. S. (2024) · Advanced Materials · doi:10.1002/adma.202403701 · Cited by 17 · see citing works
Mechanistic modeling of lipid nanoparticle formation for the delivery of nucleic acid therapeutics
Inguva, P., Mukherjee, S., Walker, P. J., Tenberg, V., Devos, C., Shin, S., Wu, Y., Santra, S., Wang, J., Singh, S., et al. (2025) · Biotechnology Advances · doi:10.1016/j.biotechadv.2025.108643 · Cited by 18 · see citing works
Elsayed, A., Jaber, N., Al-Remawi, M. M., & Abu–Salah, K. M. (2023) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2023.123360 · Cited by 17 · see citing works
- 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.
- Venue
- Biophysical Journal
- Publisher
- Elsevier BV
- Published
- 2021-07
- Volume
- 120
- Issue
- 14
- Pages
- 2766-2770
- ISSN
- 0006-3495 (ISSN-L)
- 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
- 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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