Evaluation of PDA‑PLL Nanoparticles for siRNA Delivery and ROS Scavenging in Rat Osteoarthritis

Osteoarthritis (OA) is a prevalent chronic inflammatory disease in which elevated TNF-α and excessive reactive oxygen species (ROS) play central roles. These two pathological factors mutually reinforce each other-TNF-α induces ROS production while ROS upregulates TNF-α expression-forming a vicious cycle that propels disease progression. However, current therapies offer only symptomatic relief without halting this process. To address this, we developed polydopamine-poly(L-lysine) (PDA-PLL) nanoparticles as a dual-functional platform that combines PDA-mediated ROS scavenging with PLL-facilitated TNF-α siRNA delivery.

PDA-PLL nanoparticles were synthesized and systematically characterized, and then their gene transfection efficiency and ROS scavenging capacity were evaluated. Finally, their therapeutic efficacy against OA was assessed in chondrocytes and in animal models.

Biocompatibility was evidenced by low in-vitro cytotoxicity and the absence of systemic toxicity in rats by hematology, biochemistry, and histopathology. Agarose gel electrophoresis demonstrated their strong nucleic acid loading capability, and fluorescence imaging further revealed that PDA-PLL nanoparticles enabled highly efficient gene transfection in OA chondrocytes. PDA-PLL nanoparticles exhibited dose-dependent scavenging of O₂ ^{•-, •}OH, and H₂O₂ in cell-free assays and lowered intracellular ROS in OA chondrocytes; critically, co-delivery of TNF-α siRNA further reduced ROS versus PDA-PLL alone. Consistent with these findings, the PDA-PLL+TNF-α siRNA group showed stronger suppression of inflammatory genes, greater restoration of matrix-preserving genes, and enhanced cytoprotection compared with PDA-PLL alone. In rat OA, PDA-PLL+siRNA outperformed PDA-PLL alone, with macroscopic and histological outcomes approaching the sham group.

This work presents PDA-PLL nanoparticles as a multifunctional therapeutic system that unites efficient gene delivery with potent ROS scavenging. Their synergistic action resulted in significant protection of chondrocytes and potent therapeutic efficacy in OA models.