Lipid nanoparticles enabling gene therapies: from concepts to clinical utility
Open accessAbstract
Genetic drugs based on RNA or DNA have remarkable therapeutic potential as virtually any disease can be treated by silencing a pathological gene, expressing a beneficial protein, or by editing defective genes. However, therapies based on nucleic acid polymers require sophisticated delivery systems to deliver these macromolecules to the interior of target cells. In this study, we review progress in developing nonviral lipid nanoparticle (LNP) delivery systems that have attractive properties, including ease of manufacture, reduced immune responses, multidosing capabilities, larger payloads, and flexibility of design. LNP systems represent the most advanced delivery systems for genetic drugs as it is expected that an LNP-short interfering RNA (siRNA) formulation will receive clinical approval from the Food and Drug Administration (FDA) in 2018 for treatment of the hereditary condition transthyretin-mediated amyloidosis, a fatal condition for which there is currently no treatment. This achievement is largely due to the development of optimized ionizable cationic lipids, arguably the most important factor in the clinical success of LNP-siRNA. In addition, we highlight potential LNP applications, including targeting tissues beyond the liver and therapeutic approaches based on messenger RNA or Clustered Regularly Interspaced Short Palindromic Repeats/Cas.
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One potential mechanism of hepatocyte targeting by LNPs involves interaction of ionizable LNPs with apolipoprotein E (apoE), which mediates hepatocellular uptake through receptors such as LDLR.
“one potential mechanism of hepatocyte targeting effect by LNPs involves the interaction of ionizable LNPs with apolipoprotein E (apoE), a protein that facilitates the transport of molecules such as lipids and cholesterol.[59, 60] Binding on the surface of LNPs, apoE mediated the hepatocellular uptake of LNPs through multiple receptors, such as the low-density lipoprotein receptor (LDLR).[59, 60]”
From RNA delivery biomaterials for the treatment of genetic and rare diseases (2019) · cites this paper as [59]
The most commonly reported siRNA LNP formulation contains five key components: lipid or lipid derivatives, phospholipid, cholesterol, PEG, and payload siRNA.
“The most commonly reported siRNA LNP formulation contains five key components, which are the lipid or lipid derivatives, phospholipid, cholesterol, polyethylene glycol (PEG), and the payload siRNA.[59]”
From RNA delivery biomaterials for the treatment of genetic and rare diseases (2019) · cites this paper as [59]
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References 80 · Cited by 592
Research works printed but not linked: 1
- Fraley R, RM Straubinger, G Rule, EL Springer and D Papahadjopoulos. (1981). Liposome-mediated delivery of deoxyribonucleic acid to cells: enhanced efficiency of de- livery related to lipid composition and incubation condi- tions. Biochemistry 20:6978-6987.
- Authors
- Kulkarni, J. A., Cullis, P. R., & van der Meel, R.
- Affiliations
- University of British Columbia (CA)
- Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada.
- Corresponding author
- Kulkarni, Jayesh A.
- Venue
- Nucleic Acid Therapeutics
- Publisher
- SAGE Publications
- Published
- 2018-06
- Volume
- 28
- Issue
- 3
- Pages
- 146-157
- ISSN
- 2159-3337 (ISSN-L)
- 2159-3345
- OpenAlex
- W2801179771
- Cited by
- 592
- References
- 80
- Citations by year
- 2026: 94 · 2025: 74 · 2024: 83 · 2023: 77 · 2022: 79 · 2021: 87 · 2020: 58 · 2019: 36 · 2018: 4
- FWCI
- 4.53
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Nucleic Acid Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- TU/e Research Portal (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Utrecht University Repository (Utrecht University) (submittedVersion)
- Funders
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (14385)
- Canadian Institutes of Health Research (FDN148469, 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, non-viral gene delivery, siRNA delivery, ionizable cationic lipids, mRNA delivery, CRISPR gene editing, immunogenicity
- MeSH terms
- Animals, Cations, Clinical Trials as Topic, Humans, Hypercholesterolemia, Lipids, Liver, Melanoma, Skin Neoplasms, Virus Diseases, Genetic Therapy, Gene Transfer Techniques, Amyloid Neuropathies, Familial, RNA, Small Interfering, Nanoparticles
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