title: Polymersome delivery of siRNA and antisense oligonucleotides.
abstract: siRNA and antisense oligonucleotides, AON, have similar size and negative charge and are often packaged for in vitro delivery with cationic lipids or polymers-but exposed positive charge is problematic in vivo. Here we demonstrate loading and functional delivery of RNAi and AON with non-ionic, nano-transforming polymersomes. These degradable carriers are taken up passively by cultured cells after which the vesicles transform into micelles that allow endolysosomal escape and delivery of either siRNA into cytosol for mRNA knockdown or else AON into the nucleus for exon skipping within pre-mRNA. Polymersome-mediated knockdown appears as efficient as common cationic-lipid transfection and about half as effective as Lenti-virus after sustained selection. For AON, initial results also show that intramuscular injection into a mouse model of muscular dystrophy leads to the expected protein expression, which occurs along the entire length of muscle. The lack of cationic groups in antisense polymersomes together with initial tests of efficacy suggests broader utility of these non-viral carriers.
authors.affiliation: Department of Chemical and Biomolecular Engineering and Pennsylvania Muscle Institute, University of Pennsylvania, Philadelphia, USA.
authors.forename: Younghoon
authors.initials: Y
authors.lastname: Kim
authors.forename: Manorama
authors.initials: M
authors.lastname: Tewari
authors.forename: J David
authors.initials: JD
authors.lastname: Pajerowski
authors.forename: Shenshen
authors.initials: S
authors.lastname: Cai
authors.forename: Shamik
authors.initials: S
authors.lastname: Sen
authors.forename: Jason H
authors.initials: JH
authors.lastname: Williams
authors.forename: Jason
authors.initials: J
authors.lastname: Williams
authors.forename: Shashank R
authors.initials: SR
authors.lastname: Sirsi
authors.forename: Shashank
authors.initials: S
authors.lastname: Sirsi
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Lutz
authors.forename: Gordon
authors.initials: G
authors.lastname: Lutz
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Discher
mesh_terms: D000818:Animals; D001672:Biocompatible Materials / Q000008:administration & dosage / Q000737:chemistry; D002460:Cell Line; D002467:Cell Nucleus / Q000737:chemistry; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000737:chemistry; D016189:Dystrophin / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D034882:Lamins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018101:Mice, Inbred mdx; D018485:Muscle Fibers, Skeletal / Q000166:cytology; D053769:Nanocapsules / Q000008:administration & dosage* / Q000737:chemistry*; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage* / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics* / Q000378:metabolism
chemical_list: D001672:Biocompatible Materials; D003692:Delayed-Action Preparations; D016189:Dystrophin; D034882:Lamins; D053769:Nanocapsules; D016376:Oligonucleotides, Antisense; D034741:RNA, Small Interfering