Metabolic‐Redox Remodeling of Inflammatory Synovium by Mannose‐Modified Selenium Nanoparticles for Osteoarthritis Therapy

ABSTRACT Osteoarthritis (OA) progression is driven by persistent synovial inflammation, amplified by oxidative stress and enhanced glycolysis. Our previous study has demonstrated that glucose transporter 1 (GLUT1) plays a key role in initiating OA synovitis via regulation of glycolysis. Single‐cell RNA sequencing and tissue‐specific fluorescent reporter mice ( Prg4 GFPCreERt2 and Lyz2‐iCre;tdTomato ) reveal that GLUT1 marks a hyperinflammatory synovial state coupled to impaired selenoprotein‐dependent redox homeostasis. Accordingly, mannose‐modified selenium nanoparticles (M‐SeNPs) are developed as an intra‐articular nanotherapeutic targeting hypermetabolic synovial niches while restoring redox balance and reprogramming dysregulated metabolism. M‐SeNPs are successfully synthesized and characterized, demonstrating preferential uptake by the GLUT1 high cells. Proteomic analysis indicates that the robust anti‐inflammatory activity of M‐SeNPs stems from coordinated metabolic reprogramming and reconstitution of the endogenous antioxidant system, driven by alterations in glycolytic protein and multiple selenoproteins. In vivo, studies demonstrate that, M‐SeNPs selectively accumulate in inflamed synovial tissues, effectively alleviating OA‐associated pain and restoring joint function. Histological and immunofluorescence analyses further demonstrate pronounced chondroprotection efficacy of M‐SeNPs in OA mouse models, which is redominantly mediated by metabolic rewiring and redox homeostasis restoration in the GLUT1 high synoviocytes. Collectively, our results establish M‐SeNPs as a compelling candidate for OA treatment via selective modulation of synovial metabolic pathway.