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Peptide-siRNA nanocomplexes targeting NF-κB subunit p65 suppress nascent experimental arthritis
Hui-fang Zhou, … , Samuel A. Wickline, Christine T.N. Pham
Hui-fang Zhou, … , Samuel A. Wickline, Christine T.N. Pham
Published August 26, 2014
Citation Information: J Clin Invest. 2014;124(10):4363-4374. https://doi.org/10.1172/JCI75673.
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Technical Advance Inflammation

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

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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

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

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Figure 5

p5RHH-p65 siRNA nanoparticles downmodulate inflammatory cytokine production and the expression of p65 specifically in the joints.

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p5RHH-p65 siRNA nanoparticles downmodulate inflammatory cytokine product...
(A) Day 10 paws were homogenized, and cleared lysates were assayed for inflammatory cytokines. **P < 0.01, ***P < 0.001. (B) Paws were processed and examined for p65 and p100 mRNA expression relative to Gapdh by real-time PCR. ND, not detected. (C) Paw lysates were probed for the presence of p65, p100, p105, and RelB by Western blotting. The protein expression of p65 was attenuated in the paw lysates of p5RHH-p65 siRNA nanoparticle–treated animals, whereas expression of related NF-κB family members was relatively preserved. The analysis was repeated with a second cohort of mice treated with the same regimen, and similar results were obtained. (D) Day 10 paw sections were probed for macrophages (F4/80+; red) and p65 (green). DAPI (blue) stained nuclei. Note that p65 protein expression per single cell was decreased in the mouse treated with p5RHH-p65 siRNA nanoparticles. Scale bar: 25 μm.
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