Membrane fusogenic high-density lipoprotein nanoparticles
Membrane fusogenic high-density lipoprotein nanoparticles
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DOI：
10.1016/j.bbamem.2019.06.007
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发表时间：
2019-10-01
影响因子：
3.4
通讯作者：
Murakami, Tatsuya
中科院分区：
文献类型：
--
作者：
Kim, Hyungjin;Nobeyama, Tomohiro;Murakami, Tatsuya
在细胞中的病毒感染期间，在温和酸性pH下的膜融合自然发生，并且已经在纳米颗粒介导的药物递送领域中被利用以规避货物的内体截留。在此，我们的目的是赋予病毒样的融合活性，以高密度脂蛋白的形式约。10-nm圆盘，包含盘状脂质双层和边缘处的脂质结合蛋白的两个拷贝。一系列的HDL突变体的制备与三种脂质和细胞穿透肽（达特，penetratin，或Arg 8）融合的蛋白质的混合物。在与阴离子脂质体在pH 5.5的脂质混合测定中，一种HDL突变体显示出比已知的促融合脂质体更高的促融合活性。在活的哺乳动物细胞中，这种HDL突变体表现出高的血浆膜结合活性的存在下，独立于pH值的血清。在没有血清的情况下，一个温和的酸性pH值依赖性结合到质膜和随后的脂质之间的混合观察到这种突变体。我们提出了一种利用高密度脂蛋白脂质/蛋白质复合结构开发基于高密度脂蛋白的药物载体的新策略。
Membrane fusion under mildly acidic pH occurs naturally during viral infection in cells and has been exploited in the field of nanoparticle-mediated drug delivery to circumvent endosomal entrapment of the cargo. Herein, we aimed to confer virus-like fusogenic activity to HDL in the form of a ca. 10-nm disc comprising a discoidal lipid bilayer and two copies of a lipid-binding protein at the edge. A series of HDL mutants were prepared with a mixture of three lipids and a cell-penetrating peptide (TAT, penetratin, or Arg8) fused to the protein. In a lipid-mixing assay with anionic liposomes at pH 5.5, one HDL mutant showed the fusogenic activity higher than known fusogenic liposomes. In live mammalian cells, this HDL mutant showed high plasma membrane-binding activity in the presence of serum independent of pH. In the absence of serum, a mildly acidic pH dependency for binding to the plasma membrane and the subsequent lipid mixing between them was observed for this mutant. We propose a novel strategy to develop HDL-based drug carriers by taking advantage of the HDL lipid/protein composite structure.