Targeted knockdown of Piezo1 in synovial macrophages attenuates osteoarthritis development.

OBJECTIVE: Osteoarthritis (OA) is a prevalent degenerative joint disease worldwide. Emerging therapies targeting the crosstalk between immune/inflammatory cells and chondrocytes have shown promise. Macrophage phenotypic reprogramming represents a potential therapeutic strategy, yet the molecular mechanisms by which mechanical signals regulate macrophage plasticity remain unclear. This study aimed to investigate the role of the mechanosensitive ion channel Piezo1 in synovial macrophage polarization and its contribution to OA pathogenesis. METHODS: Histological analyses were performed on synovial tissues from human OA patients and OA mouse models to assess Piezo1 expression in macrophages. Conditional Piezo1 knockout in macrophages was established in mice to evaluate its effect on OA progression. In vitro and in vivo experiments were conducted to explore the impact of Piezo1 deletion on macrophage polarization and chondrocyte metabolism. Mechanistic studies investigated the involvement of the DRP1-cGAS-STING axis in Piezo1-mediated inflammasome activation. Furthermore, mannose-modified liposomes carrying Si-Piezo1 were constructed to selectively target and inhibit Piezo1 expression in synovial macrophages. RESULTS: Piezo1 expression was significantly upregulated in synovial macrophages from OA joints compared to healthy joints. Macrophage-specific deletion of Piezo1 markedly alleviated OA symptoms and promoted chondrocyte anabolism. Mechanistically, Piezo1 facilitated M1 macrophage polarization by activating the NLRP3 inflammasome via the DRP1-cGAS-STING pathway, which in turn accelerated chondrocyte senescence and degeneration. Targeted delivery of Si-Piezo1 nanoparticles effectively suppressed Piezo1 expression in synovial macrophages, reduced the proportion of M1 macrophages, and alleviated OA progression in vivo. CONCLUSION: Piezo1 plays a critical role in regulating synovial macrophage polarization through mechanotransduction, thereby promoting OA progression. Targeted inhibition of Piezo1 using mannose-modified nanoparticles provides a promising therapeutic strategy for OA treatment. TRANSLATIONAL POTENTIAL: By offering experimental evidence on the role and mechanism of Piezo1 in OA synovium, this study underscores the potential of Man-LNP@Si-Piezo1 as a therapeutic strategy for OA.