期刊
ACS NANO
卷 7, 期 10, 页码 8605-8615出版社
AMER CHEMICAL SOC
DOI: 10.1021/nn403311c
关键词
siRNA; endosomolysis; melittin; drug delivery; nanoparticle
类别
资金
- National Institutes of Health [U01 CA141541, DK095555, AR056223, RO1 HL073646-08]
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.
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