Orchestration of Pathological Osteoclast‐Chondrocyte Communication via Acid‐Responsive Nanotherapeutics for Articular Cartilage Regeneration

Abstract Pathological subchondral bone remodeling, characterized by aberrant osteoclastogenesis, exacerbates cartilage degeneration by disrupting osteochondral homeostasis. Here, a correlation between pathological osteoclastogenesis and oxidative stress dynamics is reported in a rat cartilage defect model. On the basis of these findings, CeO 2 @ZIF‐8 nanotherapeutics are engineered to scavenge ROS and suppress pathological osteoclastogenesis, mitigating inflammation and cartilage degeneration. The developed system integrates cerium oxide nanoparticles (CeO 2 ) into a zeolitic imidazolate framework‐8 (ZIF‐8) framework, exploiting pH‐responsive degradation for controlled release in acidic osteochondral niches. In vitro and in vivo assessments confirmed that CeO 2 @ZIF‐8 attenuated osteoclastogenesis, reduced Il‐1b expression, and elevated Spp1 levels, and these changes are correlated with improved cartilage regeneration. Multiomics analysis revealed that conditioned supernatants from CeO 2 @ZIF‐8‐treated osteoclasts exert protective effects on chondrocytes via the PI3K‐PKCs‐ERK1/2‐ Cyp1a1 axis, maintaining the chondrocyte phenotype and inhibiting apoptosis. In summary, the findings established the feasibility for targeting osteoclast‐chondrocyte communication through nanozyme‐mediated osteoclast reprogramming and provided a mechanistic understanding of orchestrate pathological communication to drive tissue regeneration.