Phycocyanin-functionalized selenium nanoparticles attenuate osteoarthritis through ferroptosis suppression and modulation of the MAPK pathway

Osteoarthritis (OA) is a widespread degenerative disorder of the joints, in which chondrocyte oxidative stress, inflammatory responses, and Ferroptosis play pivotal roles in disease progression, yet current therapeutic strategies remain largely insufficient. In this study, we developed Se@PC NPs as a nanotherapeutic and assessed its efficacy against OA by leveraging selenium's role in redox regulation and Ferroptosis inhibition along with phycocyanin's dual antioxidant and anti-inflammatory properties. The resultant Se@PC NPs demonstrated excellent stability and biocompatibility. In IL-1β-stimulated ATDC5 cells, they effectively scavenged Reactive Oxygen Species (ROS), suppressed iron accumulation and lipid peroxidation, and upregulated key ferroptosis-related proteins (GPX4 and SLC7A11). Se@PC NPs can also promote the synthesis of cartilage extracellular matrix by reducing the levels of pro-inflammatory cytokines and catabolic Enzymes. Transcriptomic analysis revealed that Se@PC NPs modulate the MAPK signaling pathway, as well as pathways associated with Ferroptosis and oxidative stress. Furthermore, Se@PC NPs preserved mitochondrial structural integrity and membrane potential, thereby alleviating mitochondrial dysfunction. In a murine model of destabilization of the medial meniscus (DMM), Se@PC NPs attenuated cartilage erosion and osteophyte formation, restored the expression of COL2A1 and GPX4, suppressed MMP13 and COX2. In summary, Se@PC NPs synergistically exert antioxidant, anti-ferroptotic, and anti-inflammatory effects, effectively delaying OA progression and presenting a promising nanotherapeutic strategy.