title: Impact of delivery systems on siRNA immune activation and RNA interference.
abstract: Small interfering RNAs (siRNAs) induce robust degradation of homologous mRNAs. Highly specific silencing of target genes makes siRNA an interesting tool in drug development. However, several non-specific effects complicate the use of RNA interference (RNAi). One of the most prevalent unspecific effects is triggering the innate immune system in mammals. In parallel, activating the immune system may open the possibility to develop dual siRNAs for treatment of a variety of diseases including cancer. Here, we show that the best use of unmodified siRNAs for RNAi and immune activation depends on the delivery system, formulation condition, sequence and siRNA design concerning ORN motifs. Testing several commercial delivery systems identified that the optimal siRNAs for dual functions should contain TLR7/8 ORN motifs at least in the antisense strand and be delivered by either Dharmafect or HiPerfect. Superfect delivery system only activates TLR7 and opens new capabilities in RNAi and immune activation.
authors: Coley Pharmaceutical GmbH, Merowingerplatz 1a, 402254 Düsseldorf, Germany. aforsbach@gmx.de
authors: Alexandra
authors: A
authors: Forsbach
authors: Christian
authors: C
authors: Müller
authors: Carmen
authors: C
authors: Montino
authors: Andrea
authors: A
authors: Kritzler
authors: Rainer
authors: R
authors: Curdt
authors: Amina
authors: A
authors: Benahmed
authors: Marion
authors: M
authors: Jurk
authors: Jörg
authors: J
authors: Vollmer
mesh_terms: D001483:Base Sequence; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D005822:Genetic Vectors; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D007114:Immunization / Q000379:methods; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D059372:Nucleotide Motifs / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics*; D051199:Toll-Like Receptor 7 / Q000235:genetics*; D051200:Toll-Like Receptor 8 / Q000235:genetics*
chemical_list: D016207:Cytokines; D016328:NF-kappa B; D034741:RNA, Small Interfering; C495348:TLR7 protein, human; C495349:TLR8 protein, human; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8