Mechanisms of Nanoparticle-Mediated siRNA Transfection by Melittin-Derived Peptides

被引：79

作者：

Hou, Kirk K. ^{[1
]}

Pan, Hua ^{[2
]}

Ratner, Lee ^{[2
]}

Schlesinger, Paul H. ^{[3
]}

Wickline, Samuel A. ^{[2
,3
,4
]}

机构：

[1] Washington Univ, Sch Med, St Louis, MO 63108 USA

[2] Washington Univ, Sch Med, Dept Med, St Louis, MO 63108 USA

[3] Washington Univ, Sch Med, Dept Cell Biol & Physiol, St Louis, MO 63108 USA

[4] Washington Univ, Sch Med, Dept Biomed Engn, St Louis, MO 63108 USA

来源：

ACS NANO | 2013年 / 7卷 / 10期

基金：

美国国家卫生研究院;

关键词：

siRNA; endosomolysis; melittin; drug delivery; nanoparticle; NF-KAPPA-B; CELL-PENETRATING-PEPTIDE; SMALL INTERFERING RNA; DOUBLE-STRANDED-RNA; ENDOCYTIC PATHWAYS; CATIONIC LIPIDS; DELIVERY; THERAPEUTICS; TOXICITY; CHALLENGES;

D O I：

10.1021/nn403311c

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

Traditional peptide-mediated siRNA transfection via peptide transduction domains exhibits limited cytoplasmic delivery of siRNA due to endosomal entrapment. This work overcomes these limitations with the use of membrane-destabilizing peptides derived from melittin for the knockdown of NFkB signaling in a model of adult T-cell leukemia/lymphoma. While the mechanism of siRNA delivery into the cytoplasmic compartment by peptide transduction domains has not been well studied, our analysis of melittin derivatives indicates that concurrent nanocomplex disassembly and peptide-mediated endosomolysis are crucial to siRNA transfection. Importantly, in the case of the most active derivative, p5RHH, this process is initiated by acidic pH, indicating that endosomal acidification after macropinocytosis can trigger siRNA release into the cytoplasm. These data provide general principles regarding nanocomplex response to endocytosis, which may guide the development of peptide/siRNA nanocomplex-based transfection.

引用

页码：8605 / 8615

页数：11

共 71 条

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