ArticleJournal of controlled release : official journal of the Controlled Release Society2019
The valency of fatty acid conjugates impacts siRNA pharmacokinetics, distribution, and efficacy in vivo.
Article in Journal of controlled release : official journal of the Controlled Release Society, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
36 citing papers in PubMed, 61 citations in OpenAlex.
- The Versatile Applications of Antisense Oligonucleotides in Modern Medicine.International journal of molecular sciences · 2026Review
- Small Interfering RNA Therapy Targeting the Long Noncoding RNA SMILR for Therapeutic Intervention in Coronary Artery Bypass Graft Failure.JACC. Basic to translational science · 2025Article
- Small Interfering RNA Carriers for Oncotherapy: A Preclinical Overview.Pharmaceutics · 2025Review
- A Therapeutic Small-Interfering RNA Potentiates Janus Kinase 1 Modulation for the Treatment of Dog Inflammatory Diseases.ACS pharmacology & translational science · 2025Article
- Widespread tissue delivery of antagomiRs via intramuscular administration.Molecular therapy. Methods & clinical development · 2025Article
- Landscape of small nucleic acid therapeutics: moving from the bench to the clinic as next-generation medicines.Signal transduction and targeted therapy · 2025Review
- Amphiphilic Oligonucleotide Derivatives-Promising Tools for Therapeutics.Pharmaceutics · 2024Review
- Recent advances in methods for quantifying the cell penetration of macromolecules.Current opinion in chemical biology · 2024Review
- Quantifying the activity profile of ASO and siRNA conjugates in glioblastoma xenograft tumors in vivo.Nucleic acids research · 2024Article
- Recent trends in the delivery of RNA drugs: Beyond the liver, more than vaccine.European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V · 2024Review
- Multispecies-targeting siRNAs for the modulation of JAK1 in the skin.Molecular therapy. Nucleic acids · 2024Article
- Single intravitreal administration of a tetravalent siRNA exhibits robust and efficient gene silencing in mouse and pig photoreceptors.Molecular therapy. Nucleic acids · 2024Article
- Structural optimization of siRNA conjugates for albumin binding achieves effective MCL1-directed cancer therapy.Nature communications · 2024Article
- Self-delivering, chemically modified CRISPR RNAs for AAV co-delivery and genome editing in vivo.Nucleic acids research · 2024Article
- Targeting RNA with synthetic oligonucleotides: Clinical success invites new challenges.Cell chemical biology · 2024Review
- Synthesis of peptide-siRNA conjugates via internal sulfonylphosphoramidate modifications and evaluation of their in vitro activity.Nucleic acids research · 2024Article
- Rational design of a JAK1-selective siRNA inhibitor for the modulation of autoimmunity in the skin.Nature communications · 2023Article
- Therapeutic Oligonucleotides: An Outlook on Chemical Strategies to Improve Endosomal Trafficking.Cells · 2023Review
- Lipid and Peptide-Oligonucleotide Conjugates for Therapeutic Purposes: From Simple Hybrids to Complex Multifunctional Assemblies.Pharmaceutics · 2023Review
- Engineered ionizable lipid siRNA conjugates enhance endosomal escape but induce toxicity in vivo.Journal of controlled release : official journal of the Controlled Release Society · 2022Article
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Lipid-conjugated small-interfering RNAs (siRNAs) exhibit accumulation and gene silencing in extrahepatic tissues, providing an opportunity to expand therapeutic siRNA utility beyond the liver. Chemically engineering lipids may further improve siRNA delivery and efficacy, but the relationship between lipid structure/configuration and siRNA pharmacodynamics is unclear. Here, we synthesized a panel of mono-, di-, and tri-meric fatty acid-conjugated siRNAs to systematically evaluate the impact of fatty acid structure and valency on siRNA clearance, distribution, and efficacy. Fatty acid valency significantly altered the physicochemical properties of conjugated siRNAs, including hydrophobicity and micelle formation, which affected distribution. Trivalent lipid-conjugated siRNAs were predominantly retained at the site of injection with minimal systemic exposure, whereas monovalent lipid-conjugated siRNAs were quickly released into the circulation and accumulated primarily in kidney. Divalent lipid-conjugated siRNAs showed intermediate behavior, and preferentially accumulated in liver with functional distribution to lung, heart, and fat. The chemical structure of the conjugate, rather than overall physicochemical properties (i.e. hydrophobicity), predicted the degree of extrahepatic tissue accumulation necessary for productive gene silencing. Our findings will inform chemical engineering strategies for enhancing the extrahepatic delivery of lipophilic siRNAs.
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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.