ArticleNature biotechnology2025
Enhancing siRNA efficacy in vivo with extended nucleic acid backbones.
Article in Nature biotechnology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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Who cites it
36 citing papers in PubMed.
- Catalytic activation of human Argonaute 2 requires RNA duplex deformation.Nature structural & molecular biology · 2026Article
- Single-dose administration of therapeutic divalent siRNA targeting MECP2 prevents lethality in an MECP2 duplication mouse model.Nature communications · 2026Article
- Cas-regulation-targeting chimera enables selective and tunable control of CRISPR/Cas12a.Nucleic acids research · 2026Article
- Precision RNAi for Fibrodysplasia Ossificans Progressiva: a combinatorial, unimolecular, allele selective approach.Research square · 2026Article
- Methylene insertion reveals the importance of phosphate-phosphate distance in DNase I cleavage.RSC chemical biology · 2026Article
- Fully Modified SpyCas9 Guide RNAs Enable Robust Genome Editing In Cells and In Vivo.bioRxiv : the preprint server for biology · 2026Article
- Therapeutic delivery of albumin-binding siRNA targeting IRS2 to diverse cell types reduces mammary tumor growth.Molecular therapy : the journal of the American Society of Gene Therapy · 2026Article
- Divalent siRNA for prion disease.Nucleic acids research · 2026Article
- Reprogramming Lesional Macrophage Homeostasis via Interferon Regulatory Factor 5 Targeted siRNA Nanoimmunotherapy for Atherosclerosis.ACS nano · 2026Article
- The 2025 Oligo Meeting in Budapest: Highlights of the 21Molecular therapy. Nucleic acids · 2026Article
- Divalent siRNA for prion disease.bioRxiv : the preprint server for biology · 2026Article
- PDIA6 promotes the cell proliferation of ESCC by enhancing the disulfide bond formation in TRAF4.Cellular & molecular biology letters · 2026Article
- Organyl 5'-Phosphates in siRNA Guide Strands: Structure-Function Relationships Governing Anchoring in Argonaute 2 and Metabolic Stability.bioRxiv : the preprint server for biology · 2026Article
- Model selection in preclinical nucleic acid therapeutics research.Communications biology · 2026Review
- Advances and challenges in non-canonical nucleic acids data storage.Nature communications · 2026Review
- Chemically modified DNA aptamers and DNAzymes for expanded functional capabilities.Chemical science · 2026Review
- Presence of phosphodiester backbone, but not nucleobases, in the guide's 3' terminal region is necessary for RISC loading and target cleavage in vitro and in vivo.Nucleic acids research · 2026Article
- Nucleic acid therapeutics in neurodegenerative disorders: emerging technologies and clinical landscape.Molecular neurodegeneration advances · 2026Review
- Chemical strategies for brain delivery of genomic therapy.Nature reviews. Chemistry · 2025Review
- Potent and durable gene modulation in heart and muscle with chemically defined lipophilic siRNAs.Nucleic acids research · 2025Article
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25 authors.
Funding
Abstract
Therapeutic small interfering RNA (siRNA) requires sugar and backbone modifications to inhibit nuclease degradation. However, metabolic stabilization by phosphorothioate (PS), the only backbone chemistry used clinically, may be insufficient for targeting extrahepatic tissues. To improve oligonucleotide stabilization, we report the discovery, synthesis and characterization of extended nucleic acid (exNA) consisting of a methylene insertion between the 5'-C and 5'-OH of a nucleoside. exNA incorporation is compatible with common oligonucleotide synthetic protocols and the PS backbone, provides stabilization against 3' and 5' exonucleases and is tolerated at multiple oligonucleotide positions. A combined exNA-PS backbone enhances resistance to 3' exonuclease by ~32-fold over the conventional PS backbone and by >1,000-fold over the natural phosphodiester backbone, improving tissue exposure, tissue accumulation and efficacy in mice, both systemically and in the brain. The improved efficacy and durability imparted by exNA may enable therapeutic interventions in extrahepatic tissues, both with siRNA and with other oligonucleotides such as CRISPR guide RNA, antisense oligonucleotides, mRNA and tRNA.
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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.