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Efficient delivery of gapmer ASOs to muscle tissue will further broaden their therapeutic applications. Here, we evaluated the knockdown activity of lipid-conjugated DNA\/RNA heteroduplex oligonucleotides (HDOs) in muscle tissue. Cholesterol-conjugated HDO (Chol-HDO) exhibited effective gene suppression in both cardiac and skeletal muscles, outperforming unconjugated ASO and cholesterol-conjugated ASO (Chol-ASO). Chol-HDO and Chol-ASO showed greater binding to low-density lipoprotein (LDL); however, while Chol-ASO also exhibited enhanced binding to other serum proteins, Chol-HDO displayed weaker nonspecific interactions. Mechanistically, Chol-HDO enhanced cellular uptake through an LDL receptor-mediated mechanism. Moreover, subcellular distribution analysis revealed that the duplex structure of Chol-HDO promoted efficient nuclear delivery. Regarding safety, intravenous injection of Chol-ASO induced thrombocytopenia, whereas Chol-HDO mitigated this effect at the same dose. Ex vivo platelet activation assays confirmed that platelet activation was significantly more suppressed by Chol-HDO treatment than by Chol-ASO. Taken together, these results underscore the therapeutic potential of HDOs for safe and effective knockdown in muscle tissue, and provide a novel platform for the clinical development of gapmer ASO therapy for muscular disorders.<\/jats:p>","DOI":"10.1093\/nar\/gkag007","type":"journal-article","created":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T12:54:51Z","timestamp":1767963291000},"source":"Crossref","is-referenced-by-count":3,"title":["Heteroduplex oligonucleotide technology boosts gene knockdown in cardiac and skeletal muscles"],"prefix":"10.1093","volume":"54","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-5784-3724","authenticated-orcid":false,"given":"Sakino","family":"Matsuda-Kawabata","sequence":"first","affiliation":[{"name":"Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo , 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519 Tokyo ,","place":["Japan"]},{"name":"Center for Brain Integration 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