Taming the Achilles' Heel: A Chemical and Structural Design to Address Off-Target Effects in siRNA Therapeutics.

Rohith Pavan Parvathaneni, Nithiyanandan Krishnan, Nikolai Hempel, Oommen P Oommen, Oommen P Varghese

Abstract read

In one paragraph

Article in JACS Au, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it

0cells of the map it votes in

0citing papers in PubMed

–field-weighted citation impact

1 · What the graph read from it

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.

2 · The registry

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.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

5 authors.

Rohith Pavan ParvathaneniTranslational Chemical Biology, Science for Life Laboratory, Department of Chemistry, Ångström Laboratory, Uppsala University, 751 21 Uppsala, Sweden.

Nithiyanandan KrishnanNATA MRC, Rutherford Appleton Laboratory, Harwell, Oxon OX11 0FA, U.K.ORCID https://orcid.org/0000-0002-5651-1008

Nikolai HempelDepartment of Chemistry, Johannes Gutenberg University Mainz, Duesbergweg 10-14, 55128 Mainz, Germany.ORCID https://orcid.org/0009-0008-2448-3314

Oommen P OommenSchool of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, U.K.

Oommen P VargheseTranslational Chemical Biology, Science for Life Laboratory, Department of Chemistry, Ångström Laboratory, Uppsala University, 751 21 Uppsala, Sweden.ORCID https://orcid.org/0000-0001-8872-9928

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Off-target effects represent one of the major bottlenecks for RNA interference (RNAi) technology. To address this issue, we present a novel strategy by combining seed-region chemical modification with an extended 3'-overhang on the sense strand (SS) to mitigate SS-mediated and miRNA-like nontargeted interactions. To modify the seed-region, we developed a novel 2'-diol modification that was selectively installed at different positions within the seed-region of siRNA. For this purpose, we synthesized universal 2'-diacetate phosphoramidites that yielded a free 2'-diol functionality after standard deprotection of oligonucleotides. The 2'-diol moieties with single (positions 3-7) and dual (6 + 7) insertions in the seed-region decreased the melting temperature (

Indexed as

Chemical modificationRISC loadingsiRNAStructural modificationThermodynamic asymmetry

Identifiers

PMID41755844

DOI10.1021/jacsau.5c01765

PMCPMC12933297

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LicenceCC BY

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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.