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Sci Rep. 2019 Jan 24;9(1):442. doi: 10.1038/s41598-018-37018-3.

Development of a peptide-siRNA nanocomplex targeting NF- κB for efficient cartilage delivery.

Author information

1
Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
2
Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, MO, USA.
3
Department of Cardiovascular Sciences, University of South Florida Health Heart Institute, Morsani School of Medicine, Tampa, FL, USA.
4
Department of Cell Biology & Physiology, Washington University School of Medicine, St. Louis, MO, USA.
5
Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA. cpham@wustl.edu.
6
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA. cpham@wustl.edu.

Abstract

Delivery of therapeutic small interfering RNAs (siRNAs) in an effective dose to articular cartilage is very challenging as the cartilage dense extracellular matrix renders the chondrocytes inaccessible, even to intra-articular injections. Herein, we used a self-assembling peptidic nanoparticle (NP) platform featuring a cell penetrating peptide complexed to NF-κB p65 siRNA. We show that it efficiently and deeply penetrated human cartilage to deliver its siRNA cargo up to a depth of at least 700 μm. To simulate osteoarthritis in vitro, human articular cartilage explants were placed in culture and treated with IL-1β, a cytokine with known cartilage catabolic and pro-inflammatory effects. Exposure of peptide-siRNA NP to cartilage explants markedly suppressed p65 activation, an effect that persisted up to 3 weeks after an initial 48 h exposure to NP and in the presence of continuous IL-1β stimulation. Suppression of IL-1β-induced p65 activity attenuated chondrocyte apoptosis and maintained cartilage homeostasis. These findings confirm our previous in vivo studies in a murine model of post-traumatic osteoarthritis and suggest that the ability of peptide-siRNA NP to specifically modulate NF-κB pathway, a central regulator of the inflammatory responses in chondrocytes, may potentially mitigate the progression of cartilage degeneration.

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