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

Xufei Bian, Qian Guo, Lee-Fong Yau, Ling Yang, Xiaoyou Wang, Shikang Zhao, Shiqiong Wu, Xurong Qin, Zhi-Hong Jiang () and Chong Li ()
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Xufei Bian: Southwest University
Qian Guo: Southwest 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

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-57488-0

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