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  3. A worm-like nucleic acid nanostructure for gene delivery and endosomal escape via ClC3 ion exchanger

A worm-like nucleic acid nanostructure for gene delivery and endosomal escape via ClC3 ion exchanger

  • Sci Adv. 2026 Mar 6;12(10):eadw0891. doi: 10.1126/sciadv.adw0891.
Yu Xiao 1,  Cecilia Ka Wing Chan 1 2,  Leo Kit Cheung Lee 1,  Moldir Shyngys 1,  Yee Ting Elaine Chiu 1,  Evelyn Y Xue 1,  Kathy Oi-Lan Lui 3,  Ho Yin Edwin Chan 4,  Sharon Shui Yee Leung 5,  Xiaoqiang Yao 6,  Chung Hang Jonathan Choi 1 4 7
Affiliations

Affiliations

  • 1 Department of Biomedical Engineering, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR.
  • 2 Department of Surgery, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR.
  • 3 Department of Chemical Pathology, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR.
  • 4 School of Life Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR.
  • 5 School of Pharmacy, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR.
  • 6 School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR.
  • 7 Center for Neuromusculoskeletal Restorative Medicine, Hong Kong Science Park, Shatin, New Territories, Hong Kong SAR.
PMID: 41790895 DOI: 10.1126/sciadv.adw0891
Abstract

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+ and Cl- accumulation and eventual membrane rupture for cytosolic release, contributing to robust endosomal escape with a correlation coefficient <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-based 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.

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