ArticleNucleic acids research2025
Single alkyl phosphonate modification of the siRNA backbone in the seed region enhances specificity and therapeutic profile.
Article in Nucleic acids research, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 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
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Who cites it
6 citing papers in PubMed.
- Catalytic activation of human Argonaute 2 requires RNA duplex deformation.Nature structural & molecular biology · 2026Article
- Chemical Modification Strategies for Therapeutic Oligonucleotides: Mechanism Compatibility, Design Trade-Offs, and Translational Barriers.Molecules (Basel, Switzerland) · 2026Review
- 5'-Palmitate Lipid and Internal LNA-Piperidyl Triesters Enhance the RNA Affinity and Activity of Splice-Switching Oligonucleotides.Journal of the American Chemical Society · 2026Article
- Insights into siRNA Duplex Stability by UV Spectrophotometry Absorbance and Melting Temperature Analyses.ACS omega · 2026Article
- Acyclic serinol nucleic acid modification of siRNAs overcomes seed region mediated off-target effects while maintaining potency.Nucleic acids research · 2026Article
- Taming the Achilles' Heel: A Chemical and Structural Design to Address Off-Target Effects in siRNA Therapeutics.JACS Au · 2026Article
Corrections and comments
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Authors and funding
16 authors.
Funding
Abstract
We evaluated the effect of alkyl phosphonate linkages in enhancing the specificity and therapeutic profile of siRNA when incorporated into the seed region. siRNAs modified with a single alkyl phosphonate linkage demonstrated enhanced specificity and therapeutic profile compared to the parent siRNA. We found that these modifications are most effective when positioned at the internucleotide linkages 6-7 from the 5'-end of the guide strand. Our findings reveal that siRNAs with this modification maintain robust on-target activity both in vitro and in vivo. Importantly, differential gene expression (DGE) analysis showed a significant reduction in off-target effects across in vitro and in vivo, leading to an improved therapeutic profile. We also demonstrate enhanced safety in mice, as evidenced by reduced ALT/AST elevation and the absence of histopathological changes. This novel chemical approach to siRNA design provides impetus to advancing RNA interference-based treatments for various diseases.
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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.