title: Peptide nanoparticle delivery of charge-neutral splice-switching morpholino oligonucleotides.
abstract: Oligonucleotide analogs have provided novel therapeutics targeting various disorders. However, their poor cellular uptake remains a major obstacle for their clinical development. Negatively charged oligonucleotides, such as 2'-O-Methyl RNA and locked nucleic acids have in recent years been delivered successfully into cells through complex formation with cationic polymers, peptides, liposomes, or similar nanoparticle delivery systems. However, due to the lack of electrostatic interactions, this promising delivery method has been unsuccessful to date using charge-neutral oligonucleotide analogs. We show here that lipid-functionalized cell-penetrating peptides can be efficiently exploited for cellular transfection of the charge-neutral oligonucleotide analog phosphorodiamidate morpholino. The lipopeptides form complexes with splice-switching phosphorodiamidate morpholino oligonucleotide and can be delivered into clinically relevant cell lines that are otherwise difficult to transfect while retaining biological activity. To our knowledge, this is the first study to show delivery through complex formation of biologically active charge-neutral oligonucleotides by cationic peptides.
authors.affiliation: 1 Medical Research Council , Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge, United Kingdom .
authors.forename: Peter
authors.initials: P
authors.lastname: Järver
authors.forename: Eman M
authors.initials: EM
authors.lastname: Zaghloul
authors.forename: Andrey A
authors.initials: AA
authors.lastname: Arzumanov
authors.forename: Amer F
authors.initials: AF
authors.lastname: Saleh
authors.forename: Graham
authors.initials: G
authors.lastname: McClorey
authors.forename: Suzan M
authors.initials: SM
authors.lastname: Hammond
authors.forename: Mattias
authors.initials: M
authors.lastname: Hällbrink
authors.forename: Ülo
authors.initials: Ü
authors.lastname: Langel
authors.forename: C I Edvard
authors.initials: CI
authors.lastname: Smith
authors.forename: Matthew J A
authors.initials: MJ
authors.lastname: Wood
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Gait
authors.forename: Samir
authors.initials: S
authors.lastname: El Andaloussi
mesh_terms: D000361:Agammaglobulinemia / Q000188:drug therapy*; D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D040181:Genetic Diseases, X-Linked / Q000188:drug therapy*; D051379:Mice; D008969:Molecular Sequence Data; D060172:Morpholinos / Q000008:administration & dosage* / Q000627:therapeutic use; D009134:Muscular Atrophy, Spinal / Q000188:drug therapy*; D020388:Muscular Dystrophy, Duchenne / Q000188:drug therapy*; D053758:Nanoparticles; D010455:Peptides / Q000008:administration & dosage* / Q000737:chemistry
chemical_list: D060172:Morpholinos; D010455:Peptides