{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T07:59:09Z","timestamp":1790150349699,"version":"4.0.1"},"reference-count":43,"publisher":"SAGE Publications","license":[{"start":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T00:00:00Z","timestamp":1790035200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T00:00:00Z","timestamp":1790035200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Nucleic Acid Therapeutics"],"abstract":"<jats:title\/>\n                  <jats:p>\n                    Oligonucleotide therapeutics have great potential for the treatment of previously \u201cundruggable\u201d human diseases; however, their broad utility is limited by challenges in delivery and achieving sufficient endosomal escape. Systemic delivery of antisense oligonucleotides (ASOs) results in their primary accumulation in the liver and kidneys, limiting their effectiveness in targeting RNAs in other tissues. Conjugation to specific lipids has been employed to boost productive delivery of oligonucleotides to nonhepatic tissues such as heart and skeletal muscle. Once oligonucleotides have entered the right cell type, they then need to escape the endosomal lipid bilayer to reach their RNA targets in the nucleus and cytoplasm. In this article, we show that introducing a pH-sensitive linker in C16 lipid- and C22 lipid-conjugated ASOs increases endosomal remodeling events detected via a Galectin 9 reporter imaging assay, despite similar levels of ASO cellular uptake. Furthermore, incorporation of a pH-sensitive linker can lead to improved gene silencing\n                    <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                    . These data suggest that decoupling the lipid from the ASO is a promising approach to improve ASO endosomal escape and activity. Therefore, pH-sensitive linkers offer a novel strategy to expand the potential use of oligonucleotide therapeutics.\n                  <\/jats:p>","DOI":"10.1177\/21593337261488803","type":"journal-article","created":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T06:59:16Z","timestamp":1790146756000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["Incorporation of a pH-Sensitive Linker into Lipid\u2013ASO Conjugates Drives Increased Endosomal Membrane Remodeling Events"],"prefix":"10.1177","author":[{"given":"Priyanka","family":"Mangla","sequence":"first","affiliation":[{"name":"Nucleic Acid Therapeutics, Discovery Sciences, Biopharmaceuticals R&amp;D, AstraZeneca, Gothenburg, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma","family":"Kay","sequence":"additional","affiliation":[{"name":"Assays, Profiling and Cell Sciences, Discovery Sciences, Biopharmaceuticals R&amp;D, AstraZeneca, Gothenburg, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Munson","sequence":"additional","affiliation":[{"name":"Advanced Drug Delivery, Pharmaceutical Sciences, Biopharmaceuticals R&amp;D, AstraZeneca, Gothenburg, Sweden."},{"name":"Bioscience, Research and Early Development, Respiratory and Immunology, Biopharmaceuticals R&amp;D, AstraZeneca, Gothenburg, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"van Leeuwen","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology and Safety Sciences, Biopharmaceuticals R&amp;D, AstraZeneca, Gothenburg, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathrin","family":"Stavenhagen","sequence":"additional","affiliation":[{"name":"Medicinal Chemistry, Research and Early Development, Respiratory and Immunology, Biopharmaceuticals R&amp;D, AstraZeneca, Gothenburg, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Smita","family":"Nahar","sequence":"additional","affiliation":[{"name":"Assays, Profiling and Cell Sciences, Discovery Sciences, Biopharmaceuticals R&amp;D, AstraZeneca, Gothenburg, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9953-9265","authenticated-orcid":false,"given":"Annabelle","family":"Biscans","sequence":"additional","affiliation":[{"name":"Nucleic Acid Therapeutics, Discovery Sciences, Biopharmaceuticals R&amp;D, AstraZeneca, Gothenburg, 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