Mendelian randomization-inspired targeted polyphenol nanoplatform for synergistic osteoarthritis therapy

Osteoarthritis (OA) is a debilitating joint disorder with few disease-modifying treatments. Inspired by a Mendelian randomization (MR) analysis of over 470,000 individuals that identified a causal association between green tea consumption and a reduced risk of OA, this study developed a multifunctional nanomedicine (Dex@TPNs-FA, denoted as DTF) by encapsulating dexamethasone (Dex) in self-assembled tea polyphenol nanoparticles (TPNs) modified with folic acid for targeted delivery to synovial macrophages. DTF reduced inflammation and oxidative stress, inhibited apoptosis, and promoted cartilage matrix synthesis in LPS-stimulated macrophages and IL-1β-damaged chondrocytes. Transcriptomic analysis revealed that DTF upregulated HIF1α and suppressed TNF and IL17 signaling pathways. In both MIA-induced acute and DMM-induced chronic OA models, DTF alleviated pain, reduced synovitis, and preserved cartilage integrity without systemic toxicity. This study presents a genetics-guided nanotherapeutic approach, highlighting a translational pathway from population-based evidence to targeted OA treatment.