Hydrogel Doped with Sinomenine-CeO₂ Nanoparticles for Sustained Intra-articular Therapy in Knee Osteoarthritis

Intra-articular injection has emerged as a promising approach for treating knee osteoarthritis (OA), showing notable efficacy and potential. However, the risk of side effects remains a concern with the commonly used steroid therapies in clinical practice. Here, 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 polarization. In anti-OA in vivo efficacy studies, a single intra-articular injection of SMN-CeO₂@G significantly reduces osteophyte formation, promotes subchondral bone normalization, 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, with potential for improved clinical outcomes.