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Cited by 181RNA Interference and Gene DeliveryNanoparticle-Based Drug DeliveryDNA and Nucleic Acid Chemistry

Comparison of partially and fully chemically-modified siRNA in conjugate-mediated delivery in vivo

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Hassler, Matthew R, Turanov, Anton A, Alterman, Julia F, Haraszti, Reka A, Coles, Andrew H, Osborn, Maire F, Echeverria, Dimas, Nikan, Mehran +10 more·2018·Nucleic Acids Research
DOI 10.1093/nar/gky037PMC PMC5861422
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Abstract

Small interfering RNA (siRNA)-based drugs require chemical modifications or formulation to promote stability, minimize innate immunity, and enable delivery to target tissues. Partially modified siRNAs (up to 70% of the nucleotides) provide significant stabilization in vitro and are commercially available; thus are commonly used to evaluate efficacy of bio-conjugates for in vivo delivery. In contrast, most clinically-advanced non-formulated compounds, using conjugation as a delivery strategy, are fully chemically modified (100% of nucleotides). Here, we compare partially and fully chemically modified siRNAs in conjugate mediated delivery. We show that fully modified siRNAs are retained at 100x greater levels in various tissues, independently of the nature of the conjugate or siRNA sequence, and support productive mRNA silencing. Thus, fully chemically stabilized siRNAs may provide a better platform to identify novel moieties (peptides, aptamers, small molecules) for targeted RNAi delivery.

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  • PS modifications are essential for clinically-advanced siRNA configurations.

    “PS modifications are also essential for clinically-advanced siRNA configurations1, 16.”

    From A divalent siRNA chemical scaffold for potent and sustained modulation of gene expression throughout the central nervous system (2019) · cites this paper as [16]

    The Results (page not specified) say phosphorothioate (PS) linkages were included in the tested siRNAs to improve stability and resistance to exonucleases. The Introduction (page not specified) says additional PS modifications can enhance long-term efficacy of conjugated siRNAs. Neither passage establishes that PS modifications are essential for clinically advanced siRNA configurations. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Full chemical modification of siRNAs is essential for conjugate-mediated delivery.

    “As full chemical modification of siRNAs is essential for conjugate-mediated delivery16, we used fully chemically modified asymmetric siRNAs that have a 20-base guide strand and 15-base passenger strand.”

    From A divalent siRNA chemical scaffold for potent and sustained modulation of gene expression throughout the central nervous system (2019) · cites this paper as [16]

    The Introduction (page unavailable) says full chemical stabilization is preferred for in vivo applications, not essential for conjugate-mediated delivery. It also describes marginal efficacy with conjugates tested using naked or partially modified siRNAs, so the citing sentence overstates the paper's conclusion. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

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Authors
Hassler, M. R., Turanov, A. A., Alterman, J. F., Haraszti, R. A., Coles, A. H., Osborn, M. F., Echeverria, D., Nikan, M., Salomon, W. E., Roux, L., Godinho, B. M. D. C., Davis, S. M., Morrissey, D. V., Zamore, P. D., Karumanchi, S. A., Moore, M. J., Aronin, N., & Khvorova, A.
Affiliations
  • University of Massachusetts Chan Medical School (US)
  • RNA Therapeutics Institute, University of Massachusetts Medical School, USA
  • Novartis Institute of Biomedical Research, USA
  • Beth Israel Deaconess Medical Center (US)
Corresponding author
Khvorova, Anastasia
ORCID
Venue
Nucleic Acids Research
Publisher
Oxford University Press (OUP)
Published
2018-02-08
Volume
46
Issue
5
Pages
2185-2196
ISSN
  • 0305-1048 (ISSN-L)
  • 1362-4962
DOI
10.1093/nar/gky037
PMC
PMC5861422
OpenAlex
W2792194554
Cited by
181
References
4
Citations by year
2026: 19 · 2025: 25 · 2024: 27 · 2023: 25 · 2022: 20 · 2021: 15 · 2020: 24 · 2019: 11 · 2018: 15
FWCI
5.78
Type
journal article
Language
en
Open access
Licence
Locations
  • Nucleic Acids Research (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
  • eScholarship@UMassChan (submittedVersion, cc-by-nc)
Funders
  • CHDI Foundation (A6367)
  • Bill and Melissa Gates foundation (OPP1086170)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
  • Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
Keywords
siRNA, chemical modification, RNAi delivery, siRNA stability, tissue retention, mRNA silencing, bioconjugates
MeSH terms
Animals, Cells, Cultured, Female, Genetic Vectors, HeLa Cells, Humans, Lipids, Mice, Inbred C57BL, Peptides, RNA Processing, Post-Transcriptional, Tissue Distribution, Drug Delivery Systems, RNA Interference, RNA, Small Interfering, Aptamers, Nucleotide

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