Hydrogel doped with sinomenine-CeO₂ nanoparticles for sustained intra-articular therapy in knee osteoarthritis

In this study, we developed an intra-articular injectable hydrogel drug depot (SMN-CeO₂@G) for sustained OA treatment. This hydrogel system, which carries sinomenine-loaded cerium dioxide nanoparticles (SMN-CeO₂), enhances anti-inflammatory and anti-apoptotic effects within the joint cavity. SMN-CeO₂@G features a three-dimensional network structure with an approximate pore size of 10 μm, stably encapsulating SMN-CeO₂ nanoparticles (∼75 nm). Under hydrogen peroxide (H₂O₂) exposure and simulated mechanical stress, SMN-CeO₂@G achieves a cumulative SMN release of 44.72 ± 7.83% over 48 hours, demonstrating controlled release capabilities. At an SMN concentration of 0.5 μg/mL, SMN-CeO₂@G significantly enhances proliferation, reduces apoptosis, and lowers matrix metalloproteinases-13 (MMP-13) secretion in IL-1β-induced ATDC5 chondrocytes. In the ATDC5-RAW264.7 co-culture model, SMN-CeO₂@G effectively reduces reactive oxygen species (ROS) levels, apoptosis (∼20%), and MMP13 concentrations (24.3 ± 3.1 ng/mL) in chondrocytes, likely due to the promotion of macrophages M2 polarisation. In anti-OA efficacy studies, a single intra-articular injection of SMN-CeO₂@G significantly reduces osteophyte formation, promotes subchondral bone normalisation, alleviates pain sensitivity, and lowers serum IL-1β (59.3 ± 2.4 pg/mL) and MMP-13 (23.6 ± 1.7 ng/mL) levels in OA model rats. SMN-CeO₂@G also achieves prolonged retention in the synovial fluid, with 6.7 ± 2.8% SMN still detectable at 72 hours post-injection, a factor crucial for sustained therapeutic effect. Overall, SMN-CeO₂@G presents a promising tool for intra-articular OA treatment.