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

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-?B 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??m. To simulate osteoarthritis in vitro, human articular cartilage explants were placed in culture and treated with IL-1?, 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-1? stimulation. Suppression of IL-1?-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-?B pathway, a central regulator of the inflammatory responses in chondrocytes, may potentially mitigate the progression of cartilage degeneration.

SUBMITTER: Yan H 

PROVIDER: S-EPMC6345850 | biostudies-other | 2019 Jan

REPOSITORIES: biostudies-other