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Berberine-inspired ionizable lipid for self-structure stabilization and brain targeting delivery of nucleic acid therapeutics

Author

Listed:
  • Xufei Bian

    (Southwest University
    Southern Medical University
    North Sichuan Medical College)

  • Qian Guo

    (Southwest University
    Southern Medical University)

  • Lee-Fong Yau

    (Macau University of Science and Technology)

  • Ling Yang

    (Southwest University)

  • Xiaoyou Wang

    (Southwest University)

  • Shikang Zhao

    (Southwest University)

  • Shiqiong Wu

    (Southern Medical University)

  • Xurong Qin

    (Southwest University)

  • Zhi-Hong Jiang

    (Macau University of Science and Technology)

  • Chong Li

    (Southwest University
    Southern Medical University)

Abstract

Lipid nanoparticles have shown success in targeting major organs such as the liver, spleen, and lungs, but crossing the blood-brain barrier (BBB) remains a major challenge. Effective brain-targeted delivery systems are essential for advancing gene therapy for neurological diseases but remain limited by low transport efficiency and poor nucleic acid stability. Here, we report a library of ionizable lipids based on the tetrahydroisoquinoline structure of protoberberine alkaloids, designed to improve BBB penetration via dopamine D3 receptor-mediated endocytosis. These nanoparticles offer three key advantages: enhanced brain uptake, improved nucleic acid stability through poly(A) self-assembly, and minimal immunogenicity with inherent neuroprotective properties. In murine models, they demonstrate therapeutic potential in Alzheimer’s disease, glioma, and cryptococcal meningitis. This berberine-inspired delivery system integrates precise receptor targeting with nucleic acid stabilization, offering a promising platform for brain-targeted therapeutics.

Suggested Citation

  • Xufei Bian & Qian Guo & Lee-Fong Yau & Ling Yang & Xiaoyou Wang & Shikang Zhao & Shiqiong Wu & Xurong Qin & Zhi-Hong Jiang & Chong Li, 2025. "Berberine-inspired ionizable lipid for self-structure stabilization and brain targeting delivery of nucleic acid therapeutics," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57488-0
    DOI: 10.1038/s41467-025-57488-0
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    1. Angela M. Crist & Kelly M. Hinkle & Xue Wang & Christina M. Moloney & Billie J. Matchett & Sydney A. Labuzan & Isabelle Frankenhauser & Nkem O. Azu & Amanda M. Liesinger & Elizabeth R. Lesser & Daniel, 2021. "Transcriptomic analysis to identify genes associated with selective hippocampal vulnerability in Alzheimer’s disease," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    2. Xuexiang Han & Ningqiang Gong & Lulu Xue & Margaret M. Billingsley & Rakan El-Mayta & Sarah J. Shepherd & Mohamad-Gabriel Alameh & Drew Weissman & Michael J. Mitchell, 2023. "Ligand-tethered lipid nanoparticles for targeted RNA delivery to treat liver fibrosis," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    3. Lin-Ping Wu & Davoud Ahmadvand & Junan Su & Arnaldur Hall & Xiaolong Tan & Z. Shadi Farhangrazi & S. Moein Moghimi, 2019. "Crossing the blood-brain-barrier with nanoligand drug carriers self-assembled from a phage display peptide," Nature Communications, Nature, vol. 10(1), pages 1-16, December.
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