2. Academic Validation
  3. Berberine-inspired ionizable lipid for self-structure stabilization and brain targeting delivery of nucleic acid therapeutics

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

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. zhjiang@must.edu.mo.
  • 6 Engineering Research Center of Coptis Development & Utilization, Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Chongqing, 400715, PR China. chongli@swu.edu.cn.
  • 7 Guangdong-Hong Kong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, PR China. chongli@swu.edu.cn.
  • # 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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