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IT administration was compared with intravenous (IV) injection by assessing pharmacokinetics, biodistribution, tissue localization, and immunological effects in mice. Fluorescent hybridization assays demonstrated that IT instillation delivered SQY51 into the bloodstream, confirming systemic absorption via the pulmonary route. Compared with IV injection, IT administration produced lower peak plasma concentrations, slower clearance, and prolonged detection. Tissue distribution analysis showed higher lung accumulation but reduced levels in the kidney, heart, and diaphragm, indicating route-dependent targeting. Histological and molecular analyses showed preserved lung architecture and no significant inflammation after IT delivery. Unlike carbon black, a known inflammatory agent, SQY51 did not induce pro-inflammatory cytokine expression ex vivo or in vitro using RAW264.7 macrophages. Immunohistochemistry confirmed SQY51 uptake in CD68+CD11b+ lung macrophages. Additionally, bronchoalveolar lavage fluid analysis by in situ hybridization and immunofluorescence revealed SQY51 internalization by alveolar macrophages with retention in lysosomes. A single 25 mg\/kg pulmonary dose was safe and well-tolerated, with no adverse structural or immune effects. These findings support IT instillation as a feasible alternative for systemic delivery of tcDNA-ASOs.<\/jats:p>","DOI":"10.1093\/narmme\/ugag001","type":"journal-article","created":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T12:58:50Z","timestamp":1769086730000},"source":"Crossref","is-referenced-by-count":1,"title":["Systemic distribution of tricyclo-DNA antisense oligonucleotide following intratracheal instillation in the mouse"],"prefix":"10.1093","volume":"3","author":[{"given":"J\u00e9r\u00e9my","family":"Laurent","sequence":"first","affiliation":[{"name":"U1179 INSERM, END-ICAP, PHARMAColigo, UFR des Sciences de la Sant\u00e9-Simone Veil, Universit\u00e9 de Versailles Saint-Quentin-en-Yvelines , 78180 Montigny-le-Bretonneux ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0997-1367","authenticated-orcid":false,"given":"Therese B","family":"Deramaudt","sequence":"additional","affiliation":[{"name":"U1179 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Therapeutics , 78280 Guyancourt ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis","family":"Garcia","sequence":"additional","affiliation":[{"name":"U1179 INSERM, END-ICAP, PHARMAColigo, UFR des Sciences de la Sant\u00e9-Simone Veil, Universit\u00e9 de Versailles Saint-Quentin-en-Yvelines , 78180 Montigny-le-Bretonneux ,","place":["France"]},{"name":"SQY Therapeutics , 78280 Guyancourt ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcel","family":"Bonay","sequence":"additional","affiliation":[{"name":"U1179 INSERM, END-ICAP, PHARMAColigo, UFR des Sciences de la Sant\u00e9-Simone Veil, Universit\u00e9 de Versailles Saint-Quentin-en-Yvelines , 78180 Montigny-le-Bretonneux ,","place":["France"]},{"name":"Physiology and Functional Exploration Department; Ambroise Par\u00e9 hospital and Bic\u00eatre hospital , 92100 Boulogne-Billancourt 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