Starlike Au nanoparticle unleashing siDDIT3 and photothermal power to combat ferroptosis - driven osteoarthritis.

Osteoarthritis (OA), the most common degenerative joint disease globally, has garnered increasing attention, and emerging evidence implicated ferroptosis played an important role in both its onset and progression. In this study, we identify DDIT3, a ferroptosis-related gene, from the GEO public database of OA patient data. We demonstrate that DDIT3 accelerates articular cartilage degeneration by promoting ferroptosis, making it a viable target for therapeutic intervention. Based on this ferroptosis target we selected a siRNA to realize multiple synergistic treatment and diagnostic integration of OA by further designing the starlike Au nanoparticles composite system. These nanoparticles modified by chitosan showing positive charge facilitate superior cellular uptake and transfection of siDDIT3, while the unique thorn-like morphology enhancing photothermal effect of nanoparticles when stimulated by near-infrared (NIR) light, the star-shaped Au NPs generate mild heat through the photothermal effect, modulating the OA microenvironment to promote a more favorable setting for gene therapy. Furthermore, star configuration enables surface-enhanced Raman scattering (SERS), which allows for non-invasive, high-precision tracking of nanoparticle distribution. The synergistic combination of siDDIT3-loaded Au NPs and NIR-induced photothermal treatment not only improves the therapeutic outcomes for OA but it also creates a viable translational medicine paradigm, offering a novel approach to treating degenerative diseases through the integration of nanotechnology and gene therapy.