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Adv."],"published-print":{"date-parts":[[2026,3,6]]},"abstract":"<jats:p>\n                    Nanoparticle-based gene delivery can enable therapeutic applications with lower cytotoxicity than viral vectors, but its efficacy is often hampered by endosomal entrapment. We present a nucleic acid nanotechnology approach to circumvent this delivery bottleneck by adsorbing therapeutic nucleic acids (DNA, small interfering RNA, microRNA, or messenger RNA) to a gold-polydopamine nanoworm template, thereby assembling a three-dimensional worm-like nucleic acid nanostructure. Devoid of cationic groups, lipids, or mechanical stimuli, this nanostructure naturally activates the chloride voltage-gated channel 3 (ClC3) ion exchanger in endosomes given its worm-like shape; in turn, ClC3 mediates endosomal H\n                    <jats:sup>+<\/jats:sup>\n                    and Cl\n                    <jats:sup>\u2212<\/jats:sup>\n                    accumulation and eventual membrane rupture for cytosolic release, contributing to robust endosomal escape with a correlation coefficient\u00a0&lt;0.2 between the nanostructure and endosomes. We showcase in vitro gene regulation for primary macrophage polarization and mesenchymal stromal cell differentiation, ex vivo programmable mesenchymal stromal cell\u2013based therapy for kidney fibrosis, and in vivo hepatocyte delivery for treating liver injury. Our versatile nucleic acid nanostructure will empower safe and effective gene therapies.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.adw0891","type":"journal-article","created":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T18:58:34Z","timestamp":1772823514000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":3,"title":["A worm-like nucleic acid nanostructure for gene delivery and endosomal escape via ClC3 ion exchanger"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2998-1477","authenticated-orcid":true,"given":"Yu","family":"Xiao","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0251-3750","authenticated-orcid":true,"given":"Cecilia Ka 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