Imaging-Guided Macrophage-Targeted Nanotheranostics for Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by synovial infiltration of polarized M1 macrophages that secrete pro-inflammatory cytokines (TNF-α/IL-1/IL-6) and activate JAK-STAT/NF-κB pathways. These events disrupt the osteoblast-osteoclast balance to induce cartilage degradation and bone erosion. Current disease-modifying antirheumatic drugs (DMARDs), including tofacitinib, show limited efficacy due to systemic toxicity, poor bone-targeting capacity, and inability to restore bone homeostasis. To overcome these limitations, we developed a multifunctional nanoplatform (MBGN-Tofa@PDA-FA) based on magnesium-doped mesoporous bioactive glass nanoparticles (Mg-MBGNs) to codeliver the JAK inhibitor tofacitinib and osteoimmunomodulatory Mg2+/Ca2+ ions, aiming to overcome the severe systemic toxicity of free drugs. This system suppresses inflammation by polarizing macrophages from a pro-inflammatory M1 phenotype to an anti-inflammatory M2 phenotype (M1-to-M2 repolarization), and synergistically promotes osteoblast differentiation. Polydopamine (PDA) coating improves colloidal stability and enables photoacoustic imaging (PAI), while folic acid (FA) modification ensures selective uptake by folate receptor-overexpressing macrophages. By integrating imaging with targeted therapeutic delivery, this platform provides both real-time monitoring and enhanced treatment efficacy. Collectively, our strategy establishes a promising precision theranostic approach for RA by uniting targeted immunomodulation, bone regeneration, and treatment evaluation. Furthermore, in vivo evaluations demonstrated the excellent biodistribution and biosafety profile of this nanoplatform, reinforcing its strong potential for clinical translation.