PDA-PLL nanoparticles target oxidative stress in osteoarthritis

Polydopamine-poly(L-lysine) nanoparticles were developed as a dual-function approach for osteoarthritis, pairing polydopamine-mediated ROS scavenging with poly(L-lysine)-enabled delivery of TNF-α siRNA. The strategy targets a reinforcing disease pathway in which TNF-α promotes ROS production while ROS increases TNF-α expression.

The nanoparticles showed strong nucleic acid loading, with agarose gel electrophoresis indicating near-complete siRNA retention at a PDA-PLL/siRNA mass ratio of 50:1. In chondrocyte testing, PDA-PLL delivered genes with efficiency comparable to PEI while maintaining lower cytotoxicity, with chondrocyte viability remaining above 90% even at 100 μg/mL. The platform scavenged O2•−, •OH, and H2O2 in cell-free assays and reduced intracellular ROS in osteoarthritis chondrocytes, with added TNF-α siRNA producing stronger effects than PDA-PLL alone.

In cell and rat models, PDA-PLL+siRNA suppressed inflammatory and matrix-degrading markers, restored matrix-preserving genes, and improved chondrocyte survival. Cell death decreased from 16.88% in osteoarthritis chondrocytes to 2.64% with combination treatment. In rat knees, OARSI scores fell from 12.11 in untreated OA joints to 2.0 after 8 weeks of therapy with PDA-PLL+siRNA, while safety testing found no evident systemic toxicity.