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Through single\u2010cell transcriptomic profiling of human OA synovial tissues, a distinct subset of CD74\u207a macrophages is identified that displayed robust pro\u2010inflammatory transcriptional signatures, underscoring the pivotal role of macrophages in shaping the inflammatory microenvironment. To explore therapeutic opportunities, computational ligand\u2013target interaction analysis predicted luteolin as a high\u2010affinity binder of CD74. Mechanistically, luteolin suppressed CD74 expression and disrupted the assembly of the CEBPB\u2013p65 complex, thereby preventing p65 nuclear translocation and subsequent activation of the NF\u2010\u03baB signaling cascade in macrophages. To achieve targeted delivery, a nanoplatform MIF\n                    <jats:sup>79\u201086<\/jats:sup>\n                    \u2010DS\u2010PLGA\u2010Luteolin (MDSPL) is engineered by conjugating MIF\u2010mimetic peptides onto reactive oxygen species (ROS)\u2010responsive Poly(lactic\u2010co\u2010glycolic acid) (PLGA) nanoparticles, enabling selective recognition of CD74\u207a 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\u2010driven inflammation. Collectively, these findings establish CD74\u207a macrophages as a pathogenic driver of OA\u2010associated synovial inflammation and introduce MDSPL as a precision nanotherapeutic strategy with translational potential for OA management.\n                  <\/jats:p>","DOI":"10.1002\/advs.202508472","type":"journal-article","created":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T10:18:07Z","timestamp":1763720287000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Targeted Inhibition of CD74\n                    <sup>+<\/sup>\n                    Macrophages by Luteolin via CEBPB\/P65 Signaling Ameliorates Osteoarthritis Progression"],"prefix":"10.1002","volume":"13","author":[{"given":"Rui","family":"Peng","sequence":"first","affiliation":[{"name":"Department of Bone and Joint Surgery The Affiliated Nanhua Hospital Hengyang Medical School University of South China  Hengyang Hunan 421001 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