A role for peptides in overcoming endosomal entrapment in siRNA delivery - A focus on melittin

被引:77
作者
Hou, Kirk K. [1 ]
Pan, Hua [2 ]
Schlesinger, Paul H. [3 ]
Wickline, Samuel A. [2 ,3 ,4 ]
机构
[1] Washington Univ, Sch Med, Computat & Mol Biophys, 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
基金
美国国家卫生研究院;
关键词
Melittin; siRNA delivery; Endosomal escape; CELL-PENETRATING PEPTIDES; SMALL INTERFERING RNA; PHOSPHOROTHIOATE-STIMULATED UPTAKE; GENE-TRANSFER; OLIGONUCLEOTIDE DELIVERY; EFFICIENT DELIVERY; BINDING-PROTEIN; FUSION PROTEINS; IN-VITRO; TRANSFECTION;
D O I
10.1016/j.biotechadv.2015.05.005
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
siRNA has the possibility to revolutionize medicine by enabling highly specific and efficient silencing of proteins involved in disease pathogenesis. Despite nearly 20 years of research dedicated to translating siRNA from a research tool into a clinically relevant therapeutic, minimal success has been had to date. Access to RNA interference machinery located in the cytoplasm is often overlooked, but must be considered when designing the next generation of siRNA delivery strategies. Peptide transduction domains (PTDs) have demonstrated moderate siRNA transfection, which is primarily limited by endosomal entrapment. Strategies aimed at overcoming endosomal entrapment associated with peptide vectors are reviewed here, including osmotic methods, lipid conjugation, and fusogenic peptides. As an alternative to traditional PTD, the hemolytic peptide melittin exhibits the native capacity for endosomal disruption but causes cytotoxicity. However, appropriate packaging and protection of melittin with activation and release in the endosomal compartment has allowed melittin-based strategies to demonstrate both in vitro and in vivo safety and efficacy. These data suggest that melittin's membrane disruptive properties can enable safe and effective endosomolysis, building a case for melittin as a key component in a new generation of siRNA therapeutics. (C) 2015 Elsevier Inc. All rights reserved.
引用
收藏
页码:931 / 940
页数:10
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