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Inflammation after joint injury leads to joint responses that result in eventual osteoarthritis development. Blockade of inflammation, by suppressing NF-κB expression, has been shown to reduce joint injury-induced chondrocyte apoptosis and reactive synovitis in vivo. Herein, we demonstrate that the suppression of NF-κB p65 expression also significantly mitigates the acute pain sensitivity induced by mechanical injury to the joint. These results suggest that early intervention with anti-NF-κB nanotherapy mitigates both structural and pain-related outcomes, which in turn may impact the progression of post-traumatic osteoarthritis.