Docosahexaenoic Acid Conjugation Enhances Distribution and Safety of siRNA upon Local Administration in Mouse Brain
Open accessAbstract
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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Fully chemically-stabilized siRNAs conjugated to hydrophobic ligands like cholesterol, DHA, or DHA with a phosphocholine head group are successfully internalized by brain cells.
“When fully chemically-stabilized siRNAs are conjugated to hydrophobic ligands like cholesterol7, docosahexaenoic acid (DHA)8, or DHA with a phosphocholine head group10, they are successfully internalized by brain cells11.”
From A divalent siRNA chemical scaffold for potent and sustained modulation of gene expression throughout the central nervous system (2019) · cites this paper as [8]
The Results section (page not provided) reports that cholesterol-conjugated siRNA is internalized by neurons and, to a lesser extent, astrocytes; it also describes neuronal internalization of DHA-conjugated siRNA. Our copy does not report brain-cell internalization of siRNA conjugated to DHA with a phosphocholine head group, so it does not support that example. (LLM, conf=0.87)
Experimental — accuracy not yet measuredHigh local concentrations of cholesterol are toxic.
“In addition to reducing penetration and delivery homogeneity, high local concentrations of cholesterol are toxic.26,27”
From Lipid-siRNA conjugate accesses a perivascular transport mechanism and achieves widespread and durable knockdown in the central nervous system (2024) · cites this paper as [26]
The Results section reports severe toxicity with cholesterol-conjugated, fully modified siRNA above 25 µg and links it to accumulation near the injection site. The Discussion likewise attributes the observed toxicity to local retention of the conjugate. Neither passage establishes that high local concentrations of cholesterol itself are toxic. (LLM, conf=0.86)
Experimental — accuracy not yet measuredChol-siRNA cell-association prevents effective transport across large distances.
“While cholesterol conjugation has been used to promote cell uptake, our findings mirror prior studies showing that Chol-siRNA cell-association prevents effective transport across large distances.26”
From Lipid-siRNA conjugate accesses a perivascular transport mechanism and achieves widespread and durable knockdown in the central nervous system (2024) · cites this paper as [26]
The Results report that Chol-hsiRNA remains concentrated near the injection site in mouse brain and associates with myelin sheaths and nerve bundles. They say this association *may* explain its limited spread; the claim presents that proposed mechanism as established. (LLM, conf=0.84)
Experimental — accuracy not yet measuredsiRNAs are large, negatively-charged, double-stranded molecules that require formulation or chemical conjugation for delivery to tissues, especially the CNS.
“siRNAs are large, negatively-charged, double-stranded molecules that require formulation6 or chemical conjugation7–10 for delivery to tissues (especially CNS).”
From A divalent siRNA chemical scaffold for potent and sustained modulation of gene expression throughout the central nervous system (2019) · cites this paper as [8]
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- Authors
- Nikan, M., Osborn, M. F., Coles, A. H., Godinho, B. M., Hall, L. M., Haraszti, R. A., Hassler, M. R., Echeverria, D., Aronin, N., & Khvorova, A.
- Affiliations
- University of Massachusetts Chan Medical School (US)
- Corresponding author
- Khvorova, Anastasia
- ORCID
- Venue
- Molecular Therapy - Nucleic Acids
- Publisher
- Elsevier BV
- Published
- 2016
- Volume
- 5
- Issue
- 8
- Pages
- e344
- ISSN
- 2162-2531 (ISSN-L)
- PMC
- PMC5023396
- OpenAlex
- W2511735406
- Cited by
- 85
- References
- 50
- Citations by year
- 2026: 3 · 2025: 11 · 2024: 5 · 2023: 7 · 2022: 8 · 2021: 8 · 2020: 7 · 2019: 7 · 2018: 22 · 2017: 7
- FWCI
- 6.24
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Molecular Therapy — Nucleic Acids (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- eScholarship@UMassChan (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- CHDI Foundation
- National Institutes of Health (1s10od020012-01)
- National Institute of General Medical Sciences (R01GM108803)
- National Institute of Neurological Disorders and Stroke (F32NS095508)
- 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 › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- intrastriatal injection, chemically modified siRNA, cyclophilin B, neurodegenerative disease treatment, neurotoxicity, innate immune activation
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