Biomimetic Nanoplatform Integrating CeO₂ Nanozymes and Anti‐Inflammatory Peptides for Osteoarthritis Therapy

Abstract Osteoarthritis (OA) affects more than 250 million people worldwide, with current therapies focused primarily on symptom management rather than addressing underlying disease mechanisms. Here, MHTCK, a novel biomimetic nanoplatform is presented that uniquely integrates CeO₂ nanozymes with the anti‐inflammatory peptide KAFAK through the fusion of a macrophage‐synoviocyte membrane coating. Physicochemical characterization reveals that MHTCK maintains nanostability with a size of ≈ 200 nm and a surface charge of −30 mV. Compared with conventional antioxidant nanoparticles, the platform demonstrated superior cellular uptake in synoviocytes (2.8‐fold), chondrocytes (3.2‐fold), and macrophages (4.1‐fold). In vitro studies revealed that MHTCK effectively scavenged multiple ROS species by targeting mitochondria while preserving mitochondrial function as evidenced by the maintenance of ATP production, and promotion of M2 macrophage polarization. The biomimetic membrane coating enabled prolonged joint retention of up to 10 days postinjection through specific tissue‐targeting mechanisms, significantly improving pain thresholds and cartilage preservation in an OA rat model. This work demonstrates how rational integration of nanozyme technology with peptide therapeutics in a biomimetic delivery system can effectively modulate both oxidative stress and inflammation in OA, while maintaining cellular bioenergetics, providing new insights for developing targeted nanotherapeutics for inflammatory joint diseases.