Microfluidic Mixing: A General Method for Encapsulating Macromolecules in Lipid Nanoparticle Systems
Abstract
Previous work has shown that lipid nanoparticles (LNP) composed of an ionizable cationic lipid, a poly(ethylene glycol) (PEG) lipid, distearoylphosphatidylcholine (DSPC), cholesterol, and small interfering RNA (siRNA) can be efficiently manufactured employing microfluidic mixing techniques. Cryo-transmission electron microscopy (cryo-TEM) and molecular simulation studies indicate that these LNP systems exhibit a nanostructured core with periodic aqueous compartments containing siRNA. Here we examine first how the lipid composition influences the structural properties of LNP-siRNA systems produced by microfluidic mixing and, second, whether the microfluidic mixing technique can be extended to macromolecules larger than siRNA. It is shown that LNP-siRNA systems can exhibit progressively more bilayer structure as the proportion of bilayer DSPC lipid is increased, suggesting that the core of LNP-siRNA systems can exhibit a continuum of nanostructures depending on the proportions and structural preferences of component lipids. Second, it is shown that the microfluidic mixing technique can also be extended to encapsulation of much larger negatively charged polymers such mRNA (1.7 kb) or plasmid DNA (6 kb). Finally, as a demonstration of the generality of the microfluidic mixing encapsulation process, it is also demonstrated that negatively charged gold nanoparticles (5 nm diameter) can also be efficiently encapsulated in LNP containing cationic lipids. Interestingly, the nanostructure of these gold-containing LNP reveals a "currant bun" morphology as visualized by cryo-TEM. This structure is fully consistent with LNP-siRNA structure predicted by molecular modeling.
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Lipid nanoparticle-mRNA formulations manufactured by rapid mixing exhibit a stable nanostructure, in which mRNA molecules can be encapsulated in the interior core through electrostatic interactions with the lipids.
“Lipid nanoparticle–mRNA formulations manufactured by rapid mixing exhibit a stable nanostructure17,130,131, in which mRNA molecules can be encapsulated in the interior core through electrostatic interactions with the lipids17,131.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [131]
This technique allows reproducible and scalable production of lipid nanoparticle-mRNA formulations that show high encapsulation efficiency and homogeneous size distribution.
“This technique allows reproducible and scalable production of lipid nanoparticle–mRNA formulations that show high encapsulation efficiency and homogeneous size distribution17,131.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [131]
Bench-top microfluidic mixing devices are available for production of unloaded liposomes or mRNA LNPs via the ethanol-dilution principle, with potential to be scaled up for clinical or industrial purposes.
“Notably, bench-top microfluidic mixing devices are available for the production of unloaded liposomes or mRNA LNPs via this ethanol-dilution principle, with the potential to be scaled up for clinical or industrial purposes [116].”
From Three decades of messenger RNA vaccine development (2019) · cites this paper as [116]
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- Authors
- Leung, A. K. K., Tam, Y. Y. C., Chen, S., Hafez, I. M., & Cullis, P. R.
- Affiliations
- University of British Columbia (CA)
- Corresponding author
- Cullis, Pieter R.
- Venue
- The Journal of Physical Chemistry B
- Publisher
- American Chemical Society (ACS)
- Published
- 2015-07-07
- Volume
- 119
- Issue
- 28
- Pages
- 8698-8706
- ISSN
- 1520-5207 (ISSN-L)
- 1520-6106
- OpenAlex
- W2287068442
- Cited by
- 359
- References
- 24
- Citations by year
- 2026: 30 · 2025: 67 · 2024: 67 · 2023: 55 · 2022: 41 · 2021: 30 · 2020: 17 · 2019: 15 · 2018: 16 · 2017: 7 · 2016: 11 · 2015: 1
- FWCI
- 5.06
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Physical Chemistry B (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Canadian Institutes of Health Research (FRN111627)
- 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
- lipid nanoparticles, microfluidic mixing, siRNA encapsulation, cationic lipids, DSPC, PEG-lipids, lipid bilayer structure, mRNA encapsulation, plasmid DNA encapsulation, gold nanoparticles, lipid composition effects, nanostructures
- MeSH terms
- Gold, Phosphatidylcholines, Cryoelectron Microscopy, RNA, Small Interfering, Microfluidics, Microscopy, Electron, Transmission, Metal Nanoparticles
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