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In this study, we developed a tripled\u2010stranded ASO (tsASO) that is rendered inactive through complexation with two additional oligonucleotides. The key innovation is the use of partial overlap between the parent ASO and the biomarker sequence, combined with toehold\u2010mediated strand displacement, enabling precise conditional activation. The tsASO effectively triggered RNase H\u2010mediated degradation of\n                    <jats:italic>DYNC1I2<\/jats:italic>\n                    and\n                    <jats:italic>DARS1<\/jats:italic>\n                    RNAs exclusively in the presence of the\n                    <jats:italic>ERBB2<\/jats:italic>\n                    sequence. In cell\u2010free systems, the tsASO demonstrated high cleavage efficiency (up to 81%), comparable to the parent ASO efficiency, with minimal background activity in the absence of the biomarker sequence, validating the concept at the molecular level. However, in cells using lipid\u2010based transfection, the tsASO exhibited nonspecific cytotoxicity that did not correlate with biomarker presence or target gene expression. Detailed analysis showed no clear support for known sequence\u2010driven toxicity mechanisms (CpG\/TLR9, G\u2010quadruplexes) in the nonimmune cell lines, suggesting that the primary limitation is intracellular delivery rather than the tsASO design. Future work should focus on optimizing delivery platforms to achieve controlled cellular uptake and biomarker\u2010dependent release, unlocking the therapeutic potential of this conditional gene silencing approach.\n                  <\/jats:p>","DOI":"10.1002\/cbic.70521","type":"journal-article","created":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T18:43:02Z","timestamp":1788201782000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Tripled\u2010Stranded Antisense Oligonucleotide for Biomarker\u2010Activated Suppression of Essential Genes"],"prefix":"10.1002","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-9154-8406","authenticated-orcid":false,"given":"Valeriia S.","family":"Drozd","sequence":"first","affiliation":[{"name":"Nucleic acid Nanotechnology Laboratory ITMO University  Saint\u2010Petersburg Russian Federation"},{"name":"Advanced Engineering\u00a0School ITMO University  Almetyvsk Russian Federation"},{"name":"Belozersky Institute of Physico\u2010Chemical Biology Lomonosov Moscow State University  Moscow Russian Federation"},{"name":"Center for Molecular and Biological Technologies ITMO University  Saint\u2010Petersburg Russian Federation"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-5621-3199","authenticated-orcid":false,"given":"Lilia","family":"Tafran","sequence":"additional","affiliation":[{"name":"Nucleic acid Nanotechnology Laboratory ITMO University  Saint\u2010Petersburg Russian Federation"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikolay V.","family":"Zaramenskih","sequence":"additional","affiliation":[{"name":"Nucleic acid Nanotechnology Laboratory ITMO University  Saint\u2010Petersburg Russian Federation"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-7654-4694","authenticated-orcid":false,"given":"Yulia 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