A Cell-penetrating Helical Polymer For siRNA Delivery to Mammalian Cells
A Cell-penetrating Helical Polymer For siRNA Delivery to Mammalian Cells
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DOI：
10.1038/mt.2012.78
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发表时间：
2012-08-01
影响因子：
12.4
通讯作者：
Cheng, Jianjun
中科院分区：
文献类型：
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作者：
Gabrielson, Nathan P.;Lu, Hua;Cheng, Jianjun
细胞穿透肽 (CPP) 通常用于细胞内递送各种货物，包括药物、基因和短干扰 RNA (siRNA)。大多数 CPP 仅在暴露于晚期内体内部的酸性环境时才具有活性，从而促进内化载体的内体逃逸。在这里，我们描述了合成多肽 -PVBLG(n)-8 -的生成，该多肽能够采用独立于 pH 的螺旋结构。与其他 CPP 一样，PVBLG(n)-8 的螺旋结构允许多肽破坏膜的稳定性。然而，由于螺旋在 pH 2 至 pH 7.4 之间的所有生理相关 pH 值下都是稳定的，因此 PVBLG(n)-8 的膜渗透特性是不可逆的。鉴于其 pH 不敏感活性，我们的结果表明 PVBLG(n)-8 能够通过在细胞膜中形成孔来促进有效的 siRNA 递送，游离或复合的 siRNA 能够通过孔扩散。当尝试将 siRNA 递送至已证明难以转染的细胞时，这种进入细胞胞质的非特异性形式可能会很有用。
Cell-penetrating peptides (CPPs) are routinely used for intracellular delivery of a variety of cargo, including drugs, genes, and short interfering RNA (siRNA). Most CPPs are active only upon exposure to acidic environments inside of late endosomes, thereby facilitating the endosomal escape of internalized vectors. Here, we describe the generation of a synthetic polypeptide-PVBLG(n)-8-that is able to adopt a helical structure independent of pH. Like other CPPs, the helical structure of PVBLG(n)-8 allows the polypeptide to destabilize membranes. However, since the helix is stable at all physiologically relevant pH values between pH 2 and pH 7.4, the membrane permeation properties of PVBLG(n)-8 are irreversible. Given its pH-insensitive activity, our results suggest that PVBLG(n)-8 is able to facilitate efficient siRNA delivery by causing pore formation in the cell membranes through which either free or complexed siRNA is able to diffuse. This nonspecific form of entry into the cell cytosol may prove useful when trying to deliver siRNA to cells which have proven to be difficult to transfect.