ArticleMolecular therapy. Nucleic acids2020
Single-Stranded Phosphorothioated Regions Enhance Cellular Uptake of Cholesterol-Conjugated siRNA but Not Silencing Efficacy.
Article in Molecular therapy. Nucleic acids, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 39 citations in OpenAlex.
- Working So Hard: Double-Stranded RNAs That Can Perform Both Gene Activation and Gene Silencing.Chembiochem : a European journal of chemical biology · 2026Article
- Optimized chemical structure extends silencing duration of therapeutic siRNAs in dividing cancer and immune cells.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Article
- Small Interfering RNA Carriers for Oncotherapy: A Preclinical Overview.Pharmaceutics · 2025Review
- Systematic Evaluation of Position-Specific Tolerability of Seven Backbone and Ribose Modifications in Fully Chemically Stabilized siRNAs.Nucleic acid therapeutics · 2025Article
- Chemical Modifications in Nucleic Acid Therapeutics.Methods in molecular biology (Clifton, N.J.) · 2025Review
- A Manual for Genome and Transcriptome Engineering.IEEE reviews in biomedical engineering · 2025Review
- A programmable dual-targeting siRNA scaffold supports potent two-gene modulation in the central nervous system.Nucleic acids research · 2024Article
- RNAi-based drug design: considerations and future directions.Nature reviews. Drug discovery · 2024Review
- Influence of Combinations of Lipophilic and Phosphate Backbone Modifications on Cellular Uptake of Modified Oligonucleotides.Molecules (Basel, Switzerland) · 2024Article
- Dendritic amphiphilic siRNA: Selective albumin binding,Molecular therapy. Nucleic acids · 2023Article
- Engineering siRNA therapeutics: challenges and strategies.Journal of nanobiotechnology · 2023Review
- Di-valent siRNA-mediated silencing of MSH3 blocks somatic repeat expansion in mouse models of Huntington's disease.Molecular therapy : the journal of the American Society of Gene Therapy · 2023Article
- 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
- Synthesis, gene silencing activity, thermal stability, and serum stability of siRNA containing four (RSC advances · 2022Article
- Quantitative Measurement of Cytosolic and Nuclear Penetration of Oligonucleotide Therapeutics.ACS chemical biology · 2022Article
- Targeted Delivery of Immunostimulatory CpG Oligodeoxynucleotides to Antigen-Presenting Cells in Draining Lymph Nodes by Stearic Acid Modification and Nanostructurization.International journal of molecular sciences · 2022Article
- Tuning G-Quadruplex Nanostructures with Lipids. Towards Designing Hybrid Scaffolds for Oligonucleotide Delivery.International journal of molecular sciences · 2020Article
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Small interfering RNAs (siRNAs) have potential to silence virtually any disease-causing gene but require chemical modifications for delivery to the tissue and cell of interest. Previously, we demonstrated that asymmetric, phosphorothioate (PS)-modified, chemically stabilized, cholesterol-conjugated siRNAs, called hsiRNAs, support rapid cellular uptake and efficient mRNA silencing both in cultured cells and in vivo. Here, we systematically evaluated the impact of number, structure, and sequence context of PS-modified backbones on cellular uptake and RNAi-mediated silencing efficacy. We find that PS enhances cellular internalization in a sequence-dependent manner but only when present in a single-stranded but not double-stranded region. Furthermore, the observed increase in cellular internalization did not correlate with functional silencing improvement, indicating that PS-mediated uptake may drive compounds to non-productive sinks. Thus, the primary contributing factor of PS modifications to functional efficacy is likely stabilization rather than enhanced cellular uptake. A better understanding of the relative impact of different chemistries on productive versus non-productive uptake will assist in improved design of therapeutic RNAs.
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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.