Ionizable Cholesterol Analogs as the Fifth Component of Lipid Nanoparticles for Selective Targeting Delivery of mRNA

作者：Chao Liu, Yuhao Jiang, Wenliang Xue, Jinyu Liu, Zihao Wang, Jianhong Luo, Xinsong Li · 发表于：ACS Applied Materials & Interfaces · 年份：2025 · DOI：10.1021/acsami.4c14203 · 被引用次数：19 · 研究领域：RNA Interference and Gene Delivery、Lipid Membrane Structure and Behavior、Advanced biosensing and bioanalysis techniques

Lipid nanoparticles (LNP) have shown great promise in clinical applications for delivering mRNA. Targeted delivery of mRNA to particular tissues or organs is essential for precise therapeutic outcomes and minimized side effects in various disease models. However, achieving targeted delivery beyond the liver is a challenge based on current LNP formulations. In this report, we synthesized four ionizable cholesterol analogs by attaching two tertiary amine groups onto the head of a cholesterol-like structure and incorporated them as a fifth component into conventional commercial LNPs based on ALC-0315 or SM-102. Selective targeting delivery of mRNA is achieved by adjusting the proportion of the fifth component in the LNP. Specifically, a spleen-targeted 0315-Ergo-40% formulation demonstrated an impressive 95% delivery efficiency, while a lung-targeted 102-Sito-40% formulation achieved up to 78%. Moreover, when this strategy is applied to a self-developed ionizable lipid named U-101 instead of ALC-0315 or SM-102, the targeting delivery efficiencies to the spleen and lungs reach 96 and 71%, respectively. Multiple assessments suggest that inclusion of the fifth component does not compromise LNP stability, as indicated by consistent particle size, polydispersity index (PDI), and encapsulation efficiency. Furthermore, the test results of liver and kidney function and immunogenicity reveal no increase of toxicity in vivo following the introduction of the fifth component. Additional stu...