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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 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
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“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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“…tend to morph into bleb-like structures when phospholipid DSPC is employed, as DSPC has a strong propensity to form a lipid bilayer structure that would segregate into blebs under stress or over extended storage (Figure 5B), which is usually followed by the release of mRNA into the bleb space 35 .”
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“…insights into LNP organization have been obtained from in vitro cryo-TEM experiments of either onion-(Kulkarni et al., 2018) or blebbed-phase (Brader et al., 2021) LNPs. Complementary to experiments, molecular dynamics (MD) simulations can provide unique insights into structural and dynamic…”
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“Although this non-spherical morphology is not intrinsically unusual, it has been adopted by a variety of other RNA-LNPs (Kulkarni et al., 2018; Brader et al., 2021).”
BackgroundWater Content in Nanoparticles Determined by Small-Angle Neutron Scattering and Light Scattering
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Industrial Horizons in Pharmaceutical Science
Brader, M. L., Kim, H., Koo, O., Nagapudi, K., & Su, Y. (2024) · Molecular Pharmaceutics · doi:10.1021/acs.molpharmaceut.4c00544 · Cited by 5
Sarode, A., Ortiz, C., Derstepanian, T., Vargas‐Montoya, N., Patel, P., Khadse, N., Manna, S., Landis, R. F., Skaleski, J., Boeglin, L., et al. (2025) · Advanced Materials · doi:10.1002/adma.202517893 · Cited by 4
Extrahepatic Gene Editing In Vivo Using Organic Solvent‐Free Lipid Nanoparticles
Streiber, M., Liu, N., Simon, L., Adermann, F., Bachmann, V., Gath, L., Hoeppener, S., Schubert, S., Werz, O., Lapinte, V., et al. (2026) · Small · doi:10.1002/smll.202511489 · Cited by 4
“Due to the absence of cholesterol, BLNPs show only a few biphasic nanoparticles which are indicated by significant differences in the electron contrast within the nanoparticles, also known as blebs [60].”
Hashimoto, M., Yonezawa, S., Song, F., Nitta, C., Maeda, N., Tomita, K., Yokouchi, A., Koide, H., & Asai, T. (2023) · Biomaterials Science · doi:10.1039/d3bm00068k · Cited by 4
A modular polymer platform for efficient mRNA delivery in cancer immunotherapy
Lin, G., Huang, J., Li, X., Liu, Y., Juenke, T., Finstad, A., & Zhang, M. (2025) · Nanoscale Horizons · doi:10.1039/d5nh00299k · Cited by 3
Pastre, A., Brass, O., Terreux, R., & Mégy, S. (2025) · The Journal of Physical Chemistry B · doi:10.1021/acs.jpcb.5c04980 · Cited by 4
Messerian, K. O., Зверев, А. И., Kramarczyk, J. F., & Zydney, A. L. (2025) · Biotechnology and Bioengineering · doi:10.1002/bit.70089 · Cited by 3
“The LNP concentration was on the order of ~10 12 particles per mL (Brader et al. 2021).”
Replacing Helper Lipids With Cationic Lipids Enhances mRNA Lipid Nanoparticles Stability in Solution
Chen, R., Xu, L., Zhang, N., Yu, H., Wang, X., Zhai, J., Whelan, F., Elliott, P., & Zhao, C. (2025) · Advanced Science · doi:10.1002/advs.202511637 · Cited by 4
Liu, H., Vidallon, M. L. P., Trépout, S., Cagnes, M., Yepuri, N. R., Darwish, T. A., Moon, M. J., Shi, P., Walsh, A. P. G., Tabor, R. F., et al. (2025) · Small Structures · doi:10.1002/sstr.202500636 · Cited by 3
Fredericq, L., Hamouda, A. E. I., Zhong, Z., Ginderachter, J. A. V., Geest, B. G. D., & Laoui, D. (2026) · Journal of Controlled Release · doi:10.1016/j.jconrel.2026.114799 · Cited by 3
Zhen, Z., Darji, M., Lin, X., Bogner, R. H., & Lü, X. (2026) · AAPS Open · doi:10.1186/s41120-026-00146-6 · Cited by 3
Microfluidic process-property correlations of dsRNA lipid nanoparticle formulations
Geisler, P., Knorr, E., Steiniger, F., Levin, A., Hartwig, C., Schäberle, T. F., Vilcinskas, A., & Hellmann, C. (2026) · Scientific Reports · doi:10.1038/s41598-026-44095-2 · Cited by 3
“However, the particle morphologies we observed, using technical and agricultural grades of long dsRNA and lipids, were less defined and less homogeneous than those produced using pharmaceutical-grade mRNA-LNP systems 60 .”
Effect of transcript length, temperature, and lyophilization on mRNA-lipid nanoparticle stability
Chillara, M., Zhao, W., Dordick, J. S., & Przybycien, T. M. (2026) · Journal of Pharmaceutical Sciences · doi:10.1016/j.xphs.2026.104308 · Cited by 3
Mo, Y., & Zheng, G. (2026) · ACS Nano · doi:10.1021/acsnano.6c09354 · Cited by 3
Lopsided rigid dumbbell rheology from Langevin equation: A graduate tutorial
Phan-Thien, N., Pan, D., Kanso, M. A., & Giacomin, A. J. (2024) · Physics of Fluids · doi:10.1063/5.0220821 · Cited by 3
Rissanou, A. N., & Karatasos, K. (2022) · Soft Matter · doi:10.1039/d2sm00403h · Cited by 3
Claßen, R., Pouokam, E., Wickleder, M. S., Diener, M., & Mattern, A. (2022) · Royal Society Open Science · doi:10.1098/rsos.220244 · Cited by 3
“Since 2020, lipid nanoparticles (NPs) gained enormous attention, as this type of NPs is currently being used worldwide as carriers for vaccines against SARS-CoV-2 in the vaccines of Pfizer-BioNTech and Moderna [1,2].”
Rheology of mRNA-loaded lipid nanodumbbells
Kanso, M. A., Singh, S., Giacomin, A. J., & Braatz, R. D. (2025) · Physics of Fluids · doi:10.1063/5.0251449 · Cited by 3
Development and optimisation of cationic lipid nanoparticles for mRNA deliveryPreprint
Yan, D., Lu, H., Kaur, A., Fu, R., Wang, N., Teh, J. H., Lou, H., Aboagye, E. O., & Chen, R. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.02.07.524134 · Cited by 3
“In addition, as for the characterisation of the LNPs, cryo-electron microscopy (cryoEM) could be used to visualise the structure of the LNPs and identify whether the LNPs are multi-layered, in order to evaluate the efficiency of the extrusion process (70, 71).”
MethodCapillary‐Based Physicochemical Characterization of Lipid Nanoparticles
Kuzucu, E. Ü., Schittny, V., Huwyler, J., & Schwarz, M. A. (2025) · Electrophoresis · doi:10.1002/elps.70032 · Cited by 2
“Brader et al. showed that mRNA may be localized in blebs, if present, but in the case of spherical-solid LNPs, mRNA is present below the surface lipid bilayer [23].”
Massotti, V., Buffo, A., & Pisano, R. (2025) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2025.126449 · Cited by 2
Mejzini, F., Erdmann, F., Kunert, J., Lucas, H., Kollan, J., Krüger, S., & Mäder, K. (2026) · Journal of Controlled Release · doi:10.1016/j.jconrel.2026.114783 · Cited by 2
Graves, S., Jasinski, M., Olsén, E., Kamanzi, A., Zhang, Y., Leung, J., Venier-Karzis, M., Safaeesirat, A., Cullis, P. R., & Leslie, S. R. (2026) · Analytical Chemistry · doi:10.1021/acs.analchem.6c00937 · Cited by 2
The hidden half of lipid nanoparticle manufacturing: Downstream processing
Sagmeister, P., Devos, C., Udepurkar, A. P., Schwenger, A., Webb, C., McDonald, A., Berry, M., Zydney, A. L., Braatz, R. D., & Myerson, A. S. (2026) · Journal of Controlled Release · doi:10.1016/j.jconrel.2026.115189 · Cited by 2
Chen, F., Yang, J., Popoola, D. O., Yang, F., Liu, Y., Wang, D., Qin, Z. S., Chen, Z., Saba, N. F., Chen, Z. G., et al. (2025) · Advanced Science · doi:10.1002/advs.202502146 · Cited by 2
Revealing a Correlation between Structure and in vitro Activity of mRNA Lipid NanoparticlesPreprint
Chen, X., Fang, J., Ge, X., Li, M., Jiang, F., Hong, L., & Liu, Z. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.09.01.610730 · Cited by 2
“Previous studies have demonstrated that processing and storage conditions significantly impact both the structure and efficacy of mRNA-LNPs (17, 21).”
BackgroundChen, X., Ye, Y., Li, M., Zuo, T., Xie, Z., Ke, Y., Cheng, H., Hong, L., & Liu, Z. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.09.27.614859 · Cited by 2
“This bleb morphology of mRNA-LNPs has been reported in several previous studies (18, 31, 34-36), despite most structural studies on LNPs have focused on spherical particles (12, 14, 25, 37).”
MethodResultInfluentialVaccine efficacy, safety, and regulatory controls
Hillery, A. M. (2024) · Elsevier eBooks · doi:10.1016/b978-0-443-28934-7.00008-x · Cited by 1
Yakobi, S. H., & Nwodo, U. U. (2025) · Intelligent Systems with Applications · doi:10.1016/j.iswa.2025.200584 · Cited by 4
Hurst, P. J., Jia, Y., Ramsay-Burrough, S., McClellan, R. L., Arens, J. T., Khasnavis, S. R., Castillo, T. J. D., Elwakil, M. M. A., Lueckheide, M. J., Prabhu, V. M., et al. (2025) · ACS Nano · doi:10.1021/acsnano.5c07147 · Cited by 2
“34 − 47 , 102 Leal et al. 89, Recent coarse-grained simulations 62 indicate that the thermodynamic driving forces for the assembly of low molar mass CART amphiphiles with RNA involve a combination of hydrophobic/hydrophilic phase separation and coacerva-tion.”
Shkodra, B., Muglikar, A., THANGAPANDIAN, J., Schumacher, M., Binici, B., & Perrie, Y. (2025) · Pharmaceutics · doi:10.3390/pharmaceutics18010050 · Cited by 1
Jarand, C. W., Deng, Z., Brader, M. L., & Reed, W. F. (2026) · ACS Omega · doi:10.1021/acsomega.5c10266 · Cited by 2
Lipid Nanoparticles for Drug Delivery
Zhou, Y., Jiang, R., & Chen, W. (2026) · Elsevier eBooks · doi:10.1016/b978-0-443-34203-5.00003-6 · Cited by 1
Ševarika, B., Couvidou, A., Aldawod, D., Dinamarca, M. C., & McNeil, S. E. (2026) · Journal of Controlled Release · doi:10.1016/j.jconrel.2026.114859 · Cited by 1
Metadata
- 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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