Macrophage-Targeted Cyclodextrin-Based Metal-Organic Frameworks Restore Redox-Efferocytosis Coupling to Promote Osteochondral Repair in Temporomandibular Joint Osteoarthritis.

Abstract

Temporomandibular joint osteoarthritis (TMJOA) causes cartilage degeneration and jaw dysfunction, yet current treatments mainly provide symptomatic relief rather than restore the diseased joint microenvironment. Although suppressing ROS-driven oxidative stress is essential for limiting inflammatory injury, impaired clearance of accumulated apoptotic cells may perpetuate local inflammation and hinder regenerative repair. Here, single-cell RNA sequencing identifies macrophages as the dominant immune population in TMJOA and reveals a redox-inflammatory phenotype accompanied by elevated apoptotic burden but insufficient macrophage efferocytosis, indicating a pathological mismatch between oxidative stress and efferocytic clearance. To correct this mismatch, this study develops MCP@CD-MOF, a macrophage-targeting cyclodextrin metal-organic framework nanoplatform co-loaded with curcumin and pioglitazone. In vitro, MCP@CD-MOF reduces macrophage ROS accumulation and inflammatory cytokine production, enhances efferocytic uptake of apoptotic chondrocytes, and promotes matrix-regenerative macrophage-chondrocyte crosstalk. In vivo, intra-articular administration of MCP@CD-MOF preferentially accumulates in synovial macrophages, alleviates local inflammation, reduces apoptotic burden, and preserves osteochondral architecture without detectable systemic toxicity. Mechanistically, MCP@CD-MOF coordinates the FOXO1-GPX4/ERK1/2-NOX2 redox network with the FAK-DOCK1-PAK1 efferocytosis pathway. Collectively, MCP@CD-MOF integrates redox regulation with efferocytosis-driven macrophage reprogramming, providing a disease-modifying biomaterial strategy that couples inflammation resolution with osteochondral repair in TMJOA.