Lipid nanoparticle technology for therapeutic gene regulation in the liver
Open accessAbstract
Hereditary genetic disorders, cancer, and infectious diseases of the liver affect millions of people around the globe and are a major public health burden. Most contemporary treatments offer limited relief as they generally aim to alleviate disease symptoms. Targeting the root cause of diseases originating in the liver by regulating malfunctioning genes with nucleic acid-based drugs holds great promise as a therapeutic approach. However, employing nucleic acid therapeutics in vivo is challenging due to their unfavorable characteristics. Lipid nanoparticle (LNP) delivery technology is a revolutionary development that has enabled clinical translation of gene therapies. LNPs can deliver siRNA, mRNA, DNA, or gene-editing complexes, providing opportunities to treat hepatic diseases by silencing pathogenic genes, expressing therapeutic proteins, or correcting genetic defects. Here we discuss the state-of-the-art LNP technology for hepatic gene therapy including formulation design parameters, production methods, preclinical development and clinical translation.
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LNP-based in vivo gene editing has already led to investigational new drugs in clinical trials (NCT04601051).
“which has already lead to investigational new drugs in clinical trials (NCT04601051)”
From Off-target effects in CRISPR/Cas9 gene editing (2023) · cites this paper as Witzigmann et al., 2020
Table 4 in “Clinical translation of lipid nanotechnology” lists the LNP gene-editing candidate NTLA-2001, but gives its clinical stage as “Phase 1 planned,” not already in clinical trials. The table does not identify trial NCT04601051. (LLM, conf=0.86)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredViral transduction for Cas9/sgRNA delivery in cell culture may cause accumulation of off-target mutations.
“| Delivery methods improvement | Application in cell culture [89–94] | Viral transduction | May cause accumulation of off-target mutations |”
From Off-target effects in CRISPR/Cas9 gene editing (2023) · cites this paper as [92]
The section “mRNA for gene expression and genome editing” describes viral delivery of sgRNA and a repair template alongside lipid-nanoparticle delivery of Cas9 mRNA in mice. It does not address viral transduction of Cas9/sgRNA in cell culture or accumulation of off-target mutations; searches for those risks and for prolonged viral expression found no supporting passage. No page number was available in our copy. (LLM, conf=0.72)
Experimental — accuracy not yet measuredPlasmid transfection for Cas9/sgRNA delivery in cell culture may cause accumulation of off-target mutations.
“| Delivery methods improvement | Application in cell culture [89–94] | Plasmid transfection | May cause accumulation of off-target mutations |”
From Off-target effects in CRISPR/Cas9 gene editing (2023) · cites this paper as [92]
The sections on DNA delivery and mRNA-based genome editing discuss plasmid transfection and Cas9/sgRNA delivery, but do not address accumulation of off-target mutations. Searches for “off-target” and “plasmid transfection” found no passage linking that risk to plasmid delivery in cell culture. (LLM, conf=0.76)
Experimental — accuracy not yet measuredRNP electroporation for Cas9/sgRNA delivery in cell culture eliminates off-target effects.
“| Delivery methods improvement | Application in cell culture [89–94] | RNP electroporation: Rapid transfection and turnover | Eliminate off-target effects |”
From Off-target effects in CRISPR/Cas9 gene editing (2023) · cites this paper as [92]
The ‘mRNA for gene expression and genome editing’ section describes lipid-nanoparticle delivery of Cas9-encoding mRNA with sgRNA, including results in mice. Searches for RNP electroporation, rapid turnover, and off-target effects found no passage addressing whether electroporation in cell culture eliminates off-target effects. The available passages therefore do not verify the claim. (LLM, conf=0.74)
Experimental — accuracy not yet measured
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References 266 · Cited by 376
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- Authors
- Witzigmann, D., Kulkarni, J. A., Leung, J., Chen, S., Cullis, P. R., & van der Meel, R.
- Affiliations
- University of British Columbia (CA)
- Corresponding author
- Cullis, Pieter R.
- Venue
- Advanced Drug Delivery Reviews
- Publisher
- Elsevier BV
- Published
- 2020
- Volume
- 159
- Pages
- 344-363
- ISSN
- 0169-409X (ISSN-L)
- PMC
- PMC7329694
- OpenAlex
- W3040633579
- Cited by
- 376
- References
- 266
- Citations by year
- 2026: 47 · 2025: 74 · 2024: 78 · 2023: 67 · 2022: 70 · 2021: 32 · 2020: 8
- FWCI
- 4.24
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Advanced Drug Delivery Reviews (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- TU/e Research Portal (submittedVersion, other-oa)
- Funders
- Networks of Centres of Excellence of Canada
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Canadian Institutes of Health Research
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek
- 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, hepatic gene therapy, siRNA delivery, mRNA delivery, gene editing delivery, nucleic acid therapeutics, liver disease, clinical translation, preclinical drug development
- MeSH terms
- Animals, Gene Expression Regulation, Humans, Lipids, Liver, Genetic Therapy, Gene Transfer Techniques, Nanotechnology, Nanoparticles
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