title: A role for peptides in overcoming endosomal entrapment in siRNA delivery - A focus on melittin.
abstract: 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.
authors.affiliation: Computational and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63108, USA.
authors.forename: Kirk K
authors.initials: KK
authors.lastname: Hou
authors.affiliation: Department of Medicine, Washington University School of Medicine, St Louis, MO 63108, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Pan
authors.affiliation: Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63108, USA.
authors.forename: Paul H
authors.initials: PH
authors.lastname: Schlesinger
authors.affiliation: Department of Medicine, Washington University School of Medicine, St Louis, MO 63108, USA; Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63108, USA; Department of Biomedical Engineering, Washington University School of Medicine, St. Louis, MO 63108, USA. Electronic address: saw@wuphys.wustl.edu.
authors.forename: Samuel A
authors.initials: SA
authors.lastname: Wickline
mesh_terms: D011992:Endosomes / Q000378:metabolism*; D008555:Melitten / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism*; D014162:Transfection / Q000379:methods*
chemical_list: D034741:RNA, Small Interfering; D008555:Melitten
keywords: Endosomal escape; Melittin; siRNA delivery