GALA-Modified Lipid Nanoparticles for the Targeted Delivery of Plasmid DNA to the Lungs.
GALA-Modified Lipid Nanoparticles for the Targeted Delivery of Plasmid DNA to the Lungs.
复制标题
GALA 修饰的脂质纳米颗粒用于将质粒 DNA 靶向递送至肺部。
DOI：
10.1021/acs.molpharmaceut.0c00854
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Harashima H
中科院分区：
文献类型：
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作者：
Hagino Y;Khalil IA;Kimura S;Kusumoto K;Harashima H
本研究描述了脂质纳米粒(LNPs)的发展，用于高效和选择性地将质粒DNA(PDNA)输送到肺部。Gala多肽被用作靶向肺内皮细胞的配体和作为内体逃逸装置。将pDNA包裹在双层包被的LNPs中，可显著提高肺内的转染率。内层由二油酰基膦乙醇胺和硬脂化八精氨酸(STR-R8)多肽组成，外层主要是阳离子脂类，双十八烯基三甲基丙烷，与pH敏感的脂类YSK05和胆固醇混合。优化量的YSK05和GALA被用来实现高效和肺选择性的系统。优化的系统在肺中产生了高水平的基因表达(>；107RLU/mg蛋白)，具有高的肺/肝和肺/脾比率。Gala/R8的修饰和双包被设计对于基因在肺中的高效表达是必不可少的。尽管一步包衣和二步包衣制备的纳米粒具有相同的脂类含量和组成以及相同的PDNA剂量，但两步包衣的纳米粒在肺中的转染率显著高于两步包衣的情况。令人惊讶的是，一步或两步包衣对被输送到肺部的纳米颗粒的量没有影响，这表明双重包衣策略大大提高了细胞内水平的基因表达效率。
This study describes the development of lipid nanoparticles (LNPs) for the efficient and selective delivery of plasmid DNA (pDNA) to the lungs. The GALA peptide was used as a ligand to target the lung endothelium and as an endosomal escape device. Transfection activity in the lungs was significantly improved when pDNA was encapsulated in double-coated LNPs. The inner coat was composed of dioleoylphsophoethanolamine and a stearylated octaarginine (STR-R8) peptide, while the outer coat was largely a cationic lipid, di-octadecenyl-trimethylammonium propane, mixed with YSK05, a pH-sensitive lipid, and cholesterol. Optimized amounts of YSK05 and GALA were used to achieve an efficient and lung-selective system. The optimized system produced a high gene expression level in the lungs (>107RLU/mg protein) with high lung/liver and lung/spleen ratios. GALA/R8 modification and the double-coating design were indispensable for efficient gene expression in the lungs. Despite the fact that NPs prepared with 1-step or 2-step coating have the same lipid amount and composition and the same pDNA dose, the transfection activity was dramatically higher in the lungs in the case of 2-step coating. Surprisingly, 1-step or 2-step coatings had no effect on the amount of nanoparticles that were delivered to the lungs, suggesting that the double-coating strategy substantially improved the efficiency of gene expression at the intracellular level.