Nanozyme Coating-Mediated Mitochondrial Metabolic Reprogramming of Macrophages for Immunomodulatory Osseointegration in Rheumatoid Arthritis Case

Conventional titanium (Ti)-based implants often fail to achieve osseointegration in bone defects accompanied by rheumatoid arthritis (RA), primarily due to the RA pathological microenvironment, characterized by elevated reactive oxygen species (ROS) levels and hypoxia. This microenvironment induces mitochondria dysfunction and intracellular Ca²⁺ overload, facilitating macrophage polarization toward the M1 phenotype and thus impairing osteoimmunomodulatory osseointegration. To address this challenge, a nanozyme-inspired coating, featuring the deposition of MnFe₂O₄ nanoparticles onto a polydopamine (PDA)-decorated surface of microporous TiO₂, is constructed on Ti (known as MFO coating). The osteoimmunomodulatory osseointegration of the coating, both in vitro and in vivo, accompanied by RA was assessed, and the underlying mechanisms were also investigated. Due to the efficient conversion of H₂O₂ into O₂ and robust ROS-scavenging capabilities, the coating mitigates mitochondria ROS accumulation and intracellular Ca²⁺ overload induced by the pathological microenvironment, while simultaneously elevating intracellular O₂ levels, thereby preventing macrophage apoptosis. Meanwhile, by improving the microenvironment, the coating activates moderate mitophagy through the Ca²⁺-AMPK-mTOR signaling pathway, facilitating the removal of dysfunctional mitochondria and the preservation of mitochondrial dynamics and integrity. As a result, the restored mitochondria reprogram their metabolic pathway from relying on anaerobic to relying on aerobic oxidative phosphorylation, facilitating macrophage polarization toward the M2 phenotype, which not only inhibits osteoclastogenesis but also accelerates osseointegration in rats with RA. The coating presents a transformative approach to Ti-based implant design for bone defects associated with inflammatory diseases, potentially reducing the risk of revision surgery and offering a long-lasting lifespan for patients.