Efficient Delivery of Antisense Oligonucleotides Using Bioreducible Lipid Nanoparticles In Vitro and In Vivo
Open accessAbstract
The efficient delivery of antisense oligonucleotides (ASOs) to the targeted cells and organs remains a challenge, in particular, in vivo . Here, we investigated the ability of a library of biodegradable lipid nanoparticles (LNPs) in delivering ASO to both cultured human cells and animal models. We first identified three top-performing lipids through in vitro screening using GFP-expressing HEK293 cells. Next, we explored these three candidates for delivering ASO to target proprotein convertase subtilisin/kexin type 9 (PCSK9) mRNA in mice. We found that lipid 306-O12B-3 showed efficiency with the median effective dose (ED 50 ) as low as 0.034 mg·kg -1 , which is a notable improvement over the efficiency reported in the literature. No liver or kidney toxicity was observed with a dose up to 5 mg·kg -1 of this ASO/LNP formulation. The biodegradable LNPs are efficient and safe in the delivery of ASO and pave the way for clinical translation.
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The 306-O12B-3 lipid formulation mainly delivered ASO into the liver and could not cross the blood-brain barrier through intravenous injection.
“However, this lipid formulation mainly delivered the ASO into the liver and could not cross the BBB through intravenous injection.”
From Neurotransmitter-derived lipidoids (NT-lipidoids) for enhanced brain delivery through intravenous injection (2020) · cites this paper as [30]
The Results section, “Biodistribution of ASO-Loaded LNPs In Vivo” (page unavailable), reports that intravenously administered ASO/LNP complexes accumulated mainly in the liver, with 306-O12B-3 producing the strongest liver signal. The Methods section says the brain was among the organs examined, but the copy does not establish that this formulation could not cross the blood-brain barrier; predominant liver accumulation alone does not demonstrate that. (LLM, conf=0.86)
Experimental — accuracy not yet measuredLipidoid 306-O12B-3 can efficiently deliver ASO both in vitro and in vivo.
“In a recent study, we identified lipidoid 306-O12B-3 that can efficiently deliver ASO both in vitro and in vivo (30).”
From Neurotransmitter-derived lipidoids (NT-lipidoids) for enhanced brain delivery through intravenous injection (2020) · cites this paper as [30]
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- Authors
- Yang, L., Ma, F., Liu, F., Chen, J., Zhao, X., & Xu, Q.
- Affiliations
- Tufts University (US)
- Corresponding author
- Xu, Qiaobing
- Venue
- Molecular Therapy - Nucleic Acids
- Publisher
- Elsevier BV
- Published
- 2020-03
- Volume
- 19
- Pages
- 1357-1367
- ISSN
- 2162-2531 (ISSN-L)
- PMC
- PMC7036716
- OpenAlex
- W3002543944
- Cited by
- 103
- References
- 42
- Citations by year
- 2026: 14 · 2025: 16 · 2024: 21 · 2023: 18 · 2022: 15 · 2021: 12 · 2020: 7
- FWCI
- 4.22
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Molecular Therapy — Nucleic Acids (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institutes of Health (R01 EB027170-01, 1R21EB024041-01)
- 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
- antisense oligonucleotides, lipid nanoparticles, biodegradable lipids, nucleic acid delivery, PCSK9, lipid screening, in vivo delivery, toxicity, gene silencing
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