ArticleMolecular therapy. Nucleic acids2016
Docosahexaenoic Acid Conjugation Enhances Distribution and Safety of siRNA upon Local Administration in Mouse Brain.
Article in Molecular therapy. Nucleic acids, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 58 papers.
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Who cites it
58 citing papers in PubMed, 88 citations in OpenAlex.
- Covalent conjugation of TLR9 agonists to phospholipids enhances mRNA-LNP delivery efficiency and dendritic cell cross-priming.Journal of nanobiotechnology · 2026Article
- Bioconjugates for improved delivery of oligonucleotide therapeutics to the central nervous system.Advanced drug delivery reviews · 2026Review
- Strategies to Improve the Lipophilicity of Hydrophilic Macromolecular Drugs.Advanced healthcare materials · 2026Review
- Nucleic acid therapeutics in neurodegenerative disorders: emerging technologies and clinical landscape.Molecular neurodegeneration advances · 2026Review
- Pharmaceutical perspectives on oligonucleotide therapeutics and delivery systems.Pharmacological reviews · 2025Review
- Systematic analysis of siRNA and mRNA features impacting fully chemically modified siRNA efficacy.Nucleic acids research · 2025Article
- Metabolic Stability and Targeted Delivery of Oligonucleotides: Advancing RNA Therapeutics Beyond The Liver.Journal of medicinal chemistry · 2025Review
- Preventing acute neurotoxicity of CNS therapeutic oligonucleotides with the addition of CaMolecular therapy. Nucleic acids · 2024Article
- Amphiphilic Oligonucleotide Derivatives-Promising Tools for Therapeutics.Pharmaceutics · 2024Review
- Lipid-siRNA conjugate accesses perivascular transport and achieves durable knockdown throughout the central nervous system.bioRxiv : the preprint server for biology · 2024Article
- Preventing acute neurotoxicity of CNS therapeutic oligonucleotides with the addition of CabioRxiv : the preprint server for biology · 2024Article
- Quantifying the activity profile of ASO and siRNA conjugates in glioblastoma xenograft tumors in vivo.Nucleic acids research · 2024Article
- Single intravitreal administration of a tetravalent siRNA exhibits robust and efficient gene silencing in mouse and pig photoreceptors.Molecular therapy. Nucleic acids · 2024Article
- Self-delivering, chemically modified CRISPR RNAs for AAV co-delivery and genome editing in vivo.Nucleic acids research · 2024Article
- Cancer theragnostics: closing the loop for advanced personalized cancer treatment through the platform integration of therapeutics and diagnostics.Frontiers in bioengineering and biotechnology · 2024Review
- Dendritic amphiphilic siRNA: Selective albumin binding,Molecular therapy. Nucleic acids · 2023Article
- Lipid and Peptide-Oligonucleotide Conjugates for Therapeutic Purposes: From Simple Hybrids to Complex Multifunctional Assemblies.Pharmaceutics · 2023Review
- Nucleic acid drug vectors for diagnosis and treatment of brain diseases.Signal transduction and targeted therapy · 2023Review
- CNS Delivery of Nucleic Acid Therapeutics: Beyond the Blood-Brain Barrier and Towards Specific Cellular Targeting.Pharmaceutical research · 2023Review
- Expanding RNAi therapeutics to extrahepatic tissues with lipophilic conjugates.Nature biotechnology · 2022Article
Corrections and comments
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Authors and funding
10 authors at 1 institution in 1 country.
Funding
Abstract
The use of siRNA-based therapies for the treatment of neurodegenerative disease requires efficient, nontoxic distribution to the affected brain parenchyma, notably the striatum and cortex. Here, we describe the synthesis and activity of a fully chemically modified siRNA that is directly conjugated to docosahexaenoic acid (DHA), the most abundant polyunsaturated fatty acid in the mammalian brain. DHA conjugation enables enhanced siRNA retention throughout both the ipsilateral striatum and cortex following a single, intrastriatal injection (ranging from 6-60 μg). Within these tissues, DHA conjugation promotes internalization by both neurons and astrocytes. We demonstrate efficient and specific silencing of Huntingtin mRNA expression in both the ipsilateral striatum (up to 73%) and cortex (up to 51%) after 1 week. Moreover, following a bilateral intrastriatal injection (60 μg), we achieve up to 80% silencing of a secondary target, Cyclophilin B, at both the mRNA and protein level. Importantly, DHA-hsiRNAs do not induce neural cell death or measurable innate immune activation following administration of concentrations over 20 times above the efficacious dose. Thus, DHA conjugation is a novel strategy for improving siRNA activity in mouse brain, with potential to act as a new therapeutic platform for the treatment of neurodegenerative disorders.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.