Enhancing siRNA delivery by employing lipid nanoparticles
Abstract
For several decades extensive research has been conducted into the development of fusogenic lipid nanoparticles (LNPs) capable of introducing large, charged molecules into the cytoplasm of target cells. The majority of this work has focused on cationic LNPs encapsulating nucleic acids ranging from small oligonucleotides to large plasmid constructs thousands of bases long. However, since the introduction of siRNA payloads this quest for a non-viral, intracellular delivery systems has advanced significantly. Of particular importance was the demonstration that LNPs containing ionizable, dialkylamino lipids, enable potent hepatic gene silencing across species including humans. This review focuses on the evolution of this delivery system, summarizes the promising data now emerging from clinical trials and considers future directions for the platform.
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At blood pH, LNPs exhibit a net neutral surface charge but become positively charged in acidified endosomes following ApoE-mediated endocytosis by hepatocytes in vivo, resulting in endosome disruption and release of mRNA into the cytoplasm.
“At blood pH, LNPs exhibit a net neutral surface charge but become positively charged in acidified endosomes following ApoE-mediated endocytosis by hepatocytes in vivo, resulting in endosome disruption and release of mRNA into the cytoplasm.28,41,45”
From Sequence-engineered mRNA without chemical nucleoside modifications enables an effective protein therapy in large animals (2015) · cites this paper as [41]
The values obtained in nonhuman primates following intravenous administration of a reasonable dose of mRNA encapsulated in LNPs designed for hepatic delivery of nucleic acid therapeutics are very much in line with the clinical EPO values.
“These values are very much in line with those we obtained in nonhuman primates following intravenous administration of a reasonable dose of mRNA encapsulated in LNPs designed for hepatic delivery of nucleic acid therapeutics.41”
From Sequence-engineered mRNA without chemical nucleoside modifications enables an effective protein therapy in large animals (2015) · cites this paper as [41]
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Poletaeva, Y. E., Grigor, A. E., Dovydenko, I. S., & Ryabchikova, E. I. (2018) · Proceedings of the Voronezh State University of Engineering Technologies · doi:10.20914/2310-1202-2017-4-191-196
- Authors
- Hope, M. J.
- Affiliations
- Acuitas Therapeutics (Canada) (CA)
- Corresponding author
- Hope, Michael J
- Venue
- Therapeutic Delivery
- Publisher
- Informa UK Limited
- Published
- 2014-06
- Volume
- 5
- Issue
- 6
- Pages
- 663-673
- ISSN
- 2041-5990 (ISSN-L)
- 2041-6008
- OpenAlex
- W2113709410
- Cited by
- 22
- References
- 71
- Citations by year
- 2023: 1 · 2022: 1 · 2021: 3 · 2020: 1 · 2019: 3 · 2018: 4 · 2017: 3 · 2016: 3 · 2015: 3
- FWCI
- 0.28
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Therapeutic Delivery (publishedVersion)
- PubMed (publishedVersion)
- 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
- siRNA delivery, lipid nanoparticles, ionizable lipids, non-viral gene delivery, clinical trials, nucleic acid encapsulation
- MeSH terms
- Animals, Clinical Trials as Topic, Humans, Lipids, Drug Delivery Systems, Gene Silencing, RNA, Small Interfering, Nanoparticles
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