title: Peptide-siRNA nanocomplexes targeting NF-κB subunit p65 suppress nascent experimental arthritis.
abstract: The NF-κB signaling pathway is implicated in various inflammatory diseases, including rheumatoid arthritis (RA); therefore, inhibition of this pathway has the potential to ameliorate an array of inflammatory diseases. Given that NF-κB signaling is critical for many immune cell functions, systemic blockade of this pathway may lead to detrimental side effects. siRNAs coupled with a safe and effective delivery nanoplatform may afford the specificity lacking in systemic administration of small-molecule inhibitors. Here we demonstrated that a melittin-derived cationic amphipathic peptide combined with siRNA targeting the p65 subunit of NF-κB (p5RHH-p65) noncovalently self-assemble into stable nanocomplexes that home to the inflamed joints in a murine model of RA. Specifically, administration of p5RHH-p65 siRNA nanocomplexes abrogated inflammatory cytokine expression and cellular influx into the joints, protected against bone erosions, and preserved cartilage integrity. The p5RHH-p65 siRNA nanocomplexes potently suppressed early inflammatory arthritis without affecting p65 expression in off-target organs or eliciting a humoral response after serial injections. These data suggest that this self-assembling, largely nontoxic platform may have broad utility for the specific delivery of siRNA to target and limit inflammatory processes for the treatment of a variety of diseases.
authors.forename: Hui-fang
authors.initials: HF
authors.lastname: Zhou
authors.forename: Huimin
authors.initials: H
authors.lastname: Yan
authors.forename: Hua
authors.initials: H
authors.lastname: Pan
authors.forename: Kirk K
authors.initials: KK
authors.lastname: Hou
authors.forename: Antonina
authors.initials: A
authors.lastname: Akk
authors.forename: Luke E
authors.initials: LE
authors.lastname: Springer
authors.forename: Ying
authors.initials: Y
authors.lastname: Hu
authors.forename: J Stacy
authors.initials: JS
authors.lastname: Allen
authors.forename: Samuel A
authors.initials: SA
authors.lastname: Wickline
authors.forename: Christine T N
authors.initials: CT
authors.lastname: Pham
mesh_terms: D000818:Animals; D001172:Arthritis, Rheumatoid / Q000378:metabolism / Q000628:therapy*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D002356:Cartilage / Q000378:metabolism; D003167:Complement Activation; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D007249:Inflammation; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008856:Microscopy, Fluorescence; D052002:NF-kappa B p50 Subunit / Q000235:genetics*; D053761:Nanocomposites / Q000737:chemistry*; D053758:Nanoparticles / Q000737:chemistry; D036103:Nanotechnology; D010455:Peptides / Q000737:chemistry; D034741:RNA, Small Interfering / Q000378:metabolism*; D015398:Signal Transduction; D051996:Transcription Factor RelA / Q000235:genetics*
chemical_list: D016207:Cytokines; D052002:NF-kappa B p50 Subunit; D010455:Peptides; D034741:RNA, Small Interfering; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; C073701:Nfkb1 protein, mouse