ArticleNucleic acids research2019
Hydrophobicity drives the systemic distribution of lipid-conjugated siRNAs via lipid transport pathways.
Article in Nucleic acids research, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 77 papers, 1 of them a synthesis that pooled it.
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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.
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Who cites it
77 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Considerations and recommendations for assessment of plasma protein binding and drug-drug interactions for siRNA therapeutics.Nucleic acids research · 2022Pooled it
- A versatile strategy for oligonucleotide functionalization via on-support phosphitylation.Nature chemistry · 2026Article
- Albumin-binding dendrimer-conjugated siRNA enables safe and effective gene silencing throughout the central nervous system.Nucleic acids research · 2026Article
- Delivery Systems for Therapeutic Genome Editing: Challenges, Innovations, and Future Perspectives.MedComm · 2026Review
- Investigating theBioconjugate chemistry · 2026Article
- Precision RNAi for Fibrodysplasia Ossificans Progressiva: a combinatorial, unimolecular, allele selective approach.Research square · 2026Article
- Stability modification of therapeutic aptamers: from biostability bottlenecks to nuclease-resistant construct design.RSC chemical biology · 2026Review
- Model selection in preclinical nucleic acid therapeutics research.Communications biology · 2026Review
- Intradermal delivery of lipophilic siRNAs enables prolonged skin retention and sustained gene silencing in a porcine model.Nature communications · 2026Article
- RNA-based therapeutic opportunities for the treatment of kidney diseases.Nature reviews. Nephrology · 2026Review
- Design of bifunctional RNA-binding compounds that can modulate siRNA hydrophobicity for deep penetration and gene silencing in the retina.Molecular therapy. Nucleic acids · 2025Article
- Potent and durable gene modulation in heart and muscle with chemically defined lipophilic siRNAs.Nucleic acids research · 2025Article
- Biophysical and biological properties of splice-switching oligonucleotides and click conjugates containing LNA-phosphothiotriester linkages.Nucleic acids research · 2025Article
- Small Interfering RNA Carriers for Oncotherapy: A Preclinical Overview.Pharmaceutics · 2025Review
- Albumin-binding dendritic siRNA improves delivery and efficacy to solid tumors in a melanoma model.Molecular therapy. Nucleic acids · 2025Article
- Advances in locally administered nucleic acid therapeutics.Bioactive materials · 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
- piRNA28846 has the potential to be a novel RNA nucleic acid drug for ovarian cancer.NPJ precision oncology · 2025Article
- The Progress and Evolving Trends in Nucleic-Acid-Based Therapies.Biomolecules · 2025Review
17 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
12 authors.
Funding
Abstract
Efficient delivery of therapeutic RNA beyond the liver is the fundamental obstacle preventing its clinical utility. Lipid conjugation increases plasma half-life and enhances tissue accumulation and cellular uptake of small interfering RNAs (siRNAs). However, the mechanism relating lipid hydrophobicity, structure, and siRNA pharmacokinetics is unclear. Here, using a diverse panel of biologically occurring lipids, we show that lipid conjugation directly modulates siRNA hydrophobicity. When administered in vivo, highly hydrophobic lipid-siRNAs preferentially and spontaneously associate with circulating low-density lipoprotein (LDL), while less lipophilic lipid-siRNAs bind to high-density lipoprotein (HDL). Lipid-siRNAs are targeted to lipoprotein receptor-enriched tissues, eliciting significant mRNA silencing in liver (65%), adrenal gland (37%), ovary (35%), and kidney (78%). Interestingly, siRNA internalization may not be completely driven by lipoprotein endocytosis, but the extent of siRNA phosphorothioate modifications may also be a factor. Although biomimetic lipoprotein nanoparticles have been explored for the enhancement of siRNA delivery, our findings suggest that hydrophobic modifications can be leveraged to incorporate therapeutic siRNA into endogenous lipid transport pathways without the requirement for synthetic formulation.
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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.