Targeted Inhibition of CD74 ⁺ Macrophages by Luteolin via CEBPB/P65 Signaling Ameliorates Osteoarthritis Progression

Abstract Synovial inflammation represents a hallmark pathological process in osteoarthritis (OA), yet the cellular drivers orchestrating this response remain incompletely defined. Through single‐cell transcriptomic profiling of human OA synovial tissues, a distinct subset of CD74⁺ macrophages is identified that displayed robust pro‐inflammatory transcriptional signatures, underscoring the pivotal role of macrophages in shaping the inflammatory microenvironment. To explore therapeutic opportunities, computational ligand–target interaction analysis predicted luteolin as a high‐affinity binder of CD74. Mechanistically, luteolin suppressed CD74 expression and disrupted the assembly of the CEBPB–p65 complex, thereby preventing p65 nuclear translocation and subsequent activation of the NF‐κB signaling cascade in macrophages. To achieve targeted delivery, a nanoplatform MIF 79‐86 ‐DS‐PLGA‐Luteolin (MDSPL) is engineered by conjugating MIF‐mimetic peptides onto reactive oxygen species (ROS)‐responsive Poly(lactic‐co‐glycolic acid) (PLGA) nanoparticles, enabling selective recognition of CD74⁺ macrophages. In vivo, MDSPL exhibited superior efficacy over free luteolin in attenuating synovial inflammation and halting OA progression. Notably, early intervention with MDSPL yielded stronger chondroprotective effects than delayed administration, highlighting the therapeutic value of timely targeting of macrophage‐driven inflammation. Collectively, these findings establish CD74⁺ macrophages as a pathogenic driver of OA‐associated synovial inflammation and introduce MDSPL as a precision nanotherapeutic strategy with translational potential for OA management.