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State-of-the-art design and rapid-mixing production techniques of lipid nanoparticles for nucleic acid delivery
Open accessAbstract
Abstract Lipid nanoparticles (LNPs) are currently the most clinically advanced nonviral carriers for the delivery of small interfering RNA (siRNA). Free siRNA molecules suffer from unfavorable physicochemical characteristics and rapid clearance mechanisms, hampering the ability to reach the cytoplasm of target cells when administered intravenously. As a result, the therapeutic use of siRNA is crucially dependent on delivery strategies. LNPs can encapsulate siRNA to protect it from degradative endonucleases in the circulation, prevent kidney clearance, and provide a vehicle to deliver siRNA in the cell and induce its subsequent release into the cytoplasm. Here, the structure and composition of LNP–siRNA are described including how these affect their pharmacokinetic parameters and gene‐silencing activity. In addition, the evolution of LNP–siRNA production methods is discussed, as the development of rapid‐mixing platforms for the reproducible and scalable manufacturing has facilitated entry of LNP–siRNA into the clinic over the last decade. Finally, the potential of LNPs in delivering other nucleic acids, such as messenger RNA and CRISPR/Cas9 components, is highlighted alongside how a design‐of‐experiment approach may be used to improve the efficacy of LNP formulations.
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“The latter contains positively charged ionizable amine groups (at low pH) to interact with the anionic mRNA during particle formation and also facilitate membrane fusion during internalization (Evers et al., 2018, Reichmuth et al., 2016).”
From mRNA-lipid nanoparticle COVID-19 vaccines: structure and stability (2021) · cites this paper as Evers et al., 2018
In the citing paper
“Together with the mRNA, these components form particles of about 60–100 nm in size by using a rapid mixing production technique (Evers et al., 2018).”
From mRNA-lipid nanoparticle COVID-19 vaccines: structure and stability (2021) · cites this paper as Evers et al., 2018
In the citing paper
“Note that the physicochemical and structural characteristics of mRNA LNPs will depend on the lipid composition, the ratio of mRNA to the total amount of (cationic) lipids, and the LNP synthesis (for a detailed review on these parameters also see [107]).”
From Three decades of messenger RNA vaccine development (2019) · cites this paper as [107]
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Extracellular Vesicles for Therapeutic RNA Delivery
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A Peptide Barcode Based Approach for Efficient in vivo Screening of RNA Delivery SystemsPreprint
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Metadata
- Authors
- Evers, M. J. W., Kulkarni, J. A., van der Meel, R., Cullis, P. R., Vader, P., & Schiffelers, R. M.
- Affiliations
- University Medical Center Utrecht (NL)
- University of British Columbia (CA)
- Department of Clinical Chemistry and Haematology University Medical Center Utrecht Heidelberglaan 100 3584 CX Utrecht The Netherlands
- Corresponding author
- Schiffelers, Raymond M.
- Venue
- Small Methods
- Publisher
- Wiley
- Published
- 2018-04-26
- Volume
- 2
- Issue
- 9
- ISSN
- 2366-9608 (ISSN-L)
- OpenAlex
- W2799813152
- Cited by
- 332
- References
- 153
- Citations by year
- 2026: 52 · 2025: 55 · 2024: 56 · 2023: 58 · 2022: 52 · 2021: 32 · 2020: 15 · 2019: 9 · 2018: 2
- FWCI
- 5.15
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- public-domain
- onlinelibrary.wiley.com/termsAndConditions#vor (vor)
- Locations
- Small Methods (publishedVersion, public-domain)
- TU/e Research Portal (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Zenodo (CERN European Organization for Nuclear Research) (submittedVersion, other-oa)
- Utrecht University Repository (Utrecht University) (submittedVersion)
- Funders
- H2020 LEIT Nanotechnologies (721058, # 14385, # 13667)
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek
- Canadian Institutes of Health Research (148469)
- 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 › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advancements in Transdermal Drug Delivery
- Keywords
- lipid nanoparticles, siRNA delivery, non-viral gene delivery, pharmacokinetics, gene silencing, mRNA delivery, CRISPR/Cas9 delivery, scalable fabrication, experimental design, nucleic acid carriers
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