ArticleNucleic acids research2021
Small circular interfering RNAs (sciRNAs) as a potent therapeutic platform for gene-silencing.
Article in Nucleic acids research, 2021. 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, 23 citations in OpenAlex.
- A scalable platform for dumbbell siRNA production using engineeredMolecular therapy. Nucleic acids · 2026Article
- Advancing Biochemical Molecule Registration, Representation and Search for New Drug Modalities.Journal of chemical information and modeling · 2026Article
- RNA circularization preserves dynamics and enables in-cell relaxation NMR.Nucleic acids research · 2026Article
- On-oligonucleotide olefin metathesis in water.Nature communications · 2026Article
- The efficacy of oligonucleotide-based gene therapeutics in gene silencing.Theranostics · 2026Review
- Review
- Pharmaceutical perspectives on oligonucleotide therapeutics and delivery systems.Pharmacological reviews · 2025Review
- Alternative Approach to Sequence-Specific Recognition of DNA: Cooperative Stacking of Dication Dimers─Sensitivity to Compound Curvature, Aromatic Structure, and DNA Sequence.ACS chemical biology · 2025Article
- Circular RNAs in cancer.MedComm · 2025Review
- Chemical Modifications in Nucleic Acid Therapeutics.Methods in molecular biology (Clifton, N.J.) · 2025Review
- A Simple and Efficient One-Step Synthesis System for Flexible Production of Circular RNA inBiomolecules · 2024Article
- Molecular Identification of the Glutaredoxin 5 Gene That Plays Important Roles in Antioxidant Defense inInsects · 2024Article
- Optimal design of synthetic circular RNAs.Experimental & molecular medicine · 2024Review
- Self-Penetrating Oligonucleotide Derivatives: Features of Self-Assembly and Interactions with Serum and Intracellular Proteins.Pharmaceutics · 2023Article
- Cathepsin B-activatable cyclic antisense oligonucleotides for cell-specific target gene knockdownMolecular therapy. Nucleic acids · 2023Article
- Structural Modifications of siRNA Improve Its Performance In Vivo.International journal of molecular sciences · 2023Review
- CircRNAs in Malignant Tumor Radiation: The New Frontier as Radiotherapy Biomarkers.Frontiers in oncology · 2022Review
- The therapeutic prospects of N-acetylgalactosamine-siRNA conjugates.Frontiers in pharmacology · 2022Review
Corrections and comments
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Authors and funding
19 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
In order to achieve efficient therapeutic post-transcriptional gene-silencing mediated by the RNA interference (RNAi) pathway, small interfering RNAs (siRNAs) must be chemically modified. Several supra-RNA structures, with the potential to stabilize siRNAs metabolically have been evaluated for their ability to induce gene silencing, but all have limitations or have not been explored in therapeutically relevant contexts. Covalently closed circular RNA transcripts are prevalent in eukaryotes and have potential as biomarkers and disease targets, and circular RNA mimics are being explored for use as therapies. Here we report the synthesis and evaluation of small circular interfering RNAs (sciRNAs). To synthesize sciRNAs, a sense strand functionalized with the trivalent N-acetylgalactosamine (GalNAc) ligand and cyclized using 'click' chemistry was annealed to an antisense strand. This strategy was used for synthesis of small circles, but could also be used for synthesis of larger circular RNA mimics. We evaluated various sciRNA designs in vitro and in vivo. We observed improved metabolic stability of the sense strand upon circularization and off-target effects were eliminated. The 5'-(E)-vinylphosphonate modification of the antisense strand resulted in GalNAc-sciRNAs that are potent in vivo at therapeutically relevant doses. Physicochemical studies and NMR-based structural analysis, together with molecular modeling studies, shed light on the interactions of this novel class of siRNAs, which have a partial duplex character, with the RNAi machinery.
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