ArticleNucleic acids research2010
A screen of chemical modifications identifies position-specific modification by UNA to most potently reduce siRNA off-target effects.
Article in Nucleic acids research, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 93 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
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
93 citing papers in PubMed, 191 citations in OpenAlex.
- Small Activating RNAs: A Curated Database and an Overview of Rational Design Principles.Molecules (Basel, Switzerland) · 2026Review
- Catalytic activation of human Argonaute 2 requires RNA duplex deformation.Nature structural & molecular biology · 2026Article
- Therapeutic siRNA: Mechanisms, challenges, strategies, and clinical translation.Chinese medical journal · 2026Review
- Acyclic serinol nucleic acid modification of siRNAs overcomes seed region mediated off-target effects while maintaining potency.Nucleic acids research · 2026Article
- 2'-Ribose-modified nucleotides: A strategy for reducing off-target effects of oligonucleotide drugs.Molecular therapy. Nucleic acids · 2026Article
- Taming the Achilles' Heel: A Chemical and Structural Design to Address Off-Target Effects in siRNA Therapeutics.JACS Au · 2026Article
- Navigating the next frontier in biomedicine: breakthroughs and insights in nucleic acid therapeutics.Chemical science · 2026Review
- Advances in nano-delivery systems for overcoming the challenges of applying siRNA drugs in tumor therapy.Asian journal of pharmaceutical sciences · 2026Review
- MicroRNA chemical modifications in post-transcriptional gene silencing and human diseases.Molecular therapy. Nucleic acids · 2025Review
- Two-Stage Probability-Enhanced Regression on Property Matrices and LLM Embeddings Enables State-of-the-Art Prediction of Gene Knockdown by Modified siRNAs.International journal of molecular sciences · 2025Article
- Discovery of long-acting APOC3 siRNA for treating patients with hypertriglyceridemia.Nucleic acids research · 2025Article
- Modified unlocked nucleic acid (MUNA) mitigates off-target effects of small interfering RNAs.Nucleic acids research · 2025Article
- Redesigning miR-34a: structural and chemical advances in the therapeutic development of an miRNA anti-cancer agent.Biochemical Society transactions · 2025Article
- Single alkyl phosphonate modification of the siRNA backbone in the seed region enhances specificity and therapeutic profile.Nucleic acids research · 2025Article
- Pharmaceutical perspectives on oligonucleotide therapeutics and delivery systems.Pharmacological reviews · 2025Review
- Targeting CIDEB alleviates liver steatosis and fibrosis in mouse MASH models.Molecular therapy. Nucleic acids · 2025Article
- Systematic Evaluation of Position-Specific Tolerability of Seven Backbone and Ribose Modifications in Fully Chemically Stabilized siRNAs.Nucleic acid therapeutics · 2025Article
- Amide Internucleoside Linkages Suppress the MicroRNA-like Off-Target Activity of Short Interfering RNA.ACS chemical biology · 2025Article
- Chemical Modifications in Nucleic Acid Therapeutics.Methods in molecular biology (Clifton, N.J.) · 2025Review
- Developing the Strategy to Use Silk Spheres for Efficient, Targeted Delivery of Oligonucleotide Therapeutics to Cancer Cells.International journal of nanomedicine · 2025Article
33 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
13 authors at 5 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Small interfering RNAs (siRNAs) are now established as the preferred tool to inhibit gene function in mammalian cells yet trigger unintended gene silencing due to their inherent miRNA-like behavior. Such off-target effects are primarily mediated by the sequence-specific interaction between the siRNA seed regions (position 2-8 of either siRNA strand counting from the 5'-end) and complementary sequences in the 3'UTR of (off-) targets. It was previously shown that chemical modification of siRNAs can reduce off-targeting but only very few modifications have been tested leaving more to be identified. Here we developed a luciferase reporter-based assay suitable to monitor siRNA off-targeting in a high throughput manner using stable cell lines. We investigated the impact of chemically modifying single nucleotide positions within the siRNA seed on siRNA function and off-targeting using 10 different types of chemical modifications, three different target sequences and three siRNA concentrations. We found several differently modified siRNAs to exercise reduced off-targeting yet incorporation of the strongly destabilizing unlocked nucleic acid (UNA) modification into position 7 of the siRNA most potently reduced off-targeting for all tested sequences. Notably, such position-specific destabilization of siRNA-target interactions did not significantly reduce siRNA potency and is therefore well suited for future siRNA designs especially for applications in vivo where siRNA concentrations, expectedly, will be low.
Indexed as
Identifiers
What OpenQuestion holds
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.