Peptide-siRNA nanocomplexes targeting NF-κB subunit p65 suppress nascent experimental arthritis

Hui Fang Zhou, Huimin Yan, Hua Pan, Kirk K. Hou, Antonina Akk, Luke E. Springer, Ying Hu, J. Stacy Allen, Samuel A. Wickline, Christine T.N. Pham

Research output: Contribution to journalArticle

46 Scopus citations

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.

Original languageEnglish
Pages (from-to)4363-4374
Number of pages12
JournalJournal of Clinical Investigation
Volume124
Issue number10
DOIs
StatePublished - Oct 1 2014

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    Zhou, H. F., Yan, H., Pan, H., Hou, K. K., Akk, A., Springer, L. E., Hu, Y., Allen, J. S., Wickline, S. A., & Pham, C. T. N. (2014). Peptide-siRNA nanocomplexes targeting NF-κB subunit p65 suppress nascent experimental arthritis. Journal of Clinical Investigation, 124(10), 4363-4374. https://doi.org/10.1172/JCI75673