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

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 (Prg4GFPCreERt2 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 GLUT1high 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 GLUT1high synoviocytes. Collectively, our results establish M-SeNPs as a compelling candidate for OA treatment via selective modulation of synovial metabolic pathway.