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

  • Nat Commun. 2025 Mar 10;16(1):2368. doi: 10.1038/s41467-025-57488-0.
Xufei Bian  #  1  2  3 ,  Qian Guo  #  1  2 ,  Lee-Fong Yau  4 ,  Ling Yang  1 ,  Xiaoyou Wang  1 ,  Shikang Zhao  1 ,  Shiqiong Wu  2 ,  Xurong Qin  1 ,  Zhi-Hong Jiang  5 ,  Chong Li  6  7
Affiliations
  • 1. Engineering Research Center of Coptis Development & Utilization, Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Chongqing, 400715, PR China.
  • 2. Guangdong-Hong Kong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, PR China.
  • 3. Medical Imaging Key Laboratory of Sichuan Province, North Sichuan Medical College, Nanchong, 637000, Sichuan, PR China.
  • 4. State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macau, 999078, PR China.
  • 5. State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macau, 999078, PR China. [email protected].
  • 6. Engineering Research Center of Coptis Development & Utilization, Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Chongqing, 400715, PR China. [email protected].
  • 7. Guangdong-Hong Kong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, PR China. [email protected].
  • # Contributed equally.
PMID: 40064874 DOI: 10.1038/s41467-025-57488-0
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.

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