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

• DOI: 10.1038/s41467-025-57488-0
• Publication Date: 2025-03-10T15:01:05Z
• Authors: Xufei Bian; Qian Guo; Lee-Fong Yau; Ling Yang; Xiaoyou Wang; Shikang Zhao; Shiqiong Wu; Xurong Qin; Zhi-Hong Jiang; Chong Li

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