Inflammatory microenvironment-responsive “double-insurance” nanoreactors for accurate sonodynamic-chemodynamic therapy of rheumatoid arthritis

Rheumatoid arthritis is a systemic autoimmune disease, and the development of an accurate treatment modality that combines excellent efficacy with low toxicity is still a daunting challenge. Herein, we design copper ion-doped ZIF-8 nanoreactors loaded with Cu(II)Ce6 and BSA-MnO2 (BMCC), which has a "double-insurance" triggering mechanism for accurate sonodynamic and chemodynamic synergistic treatment of rheumatoid arthritis. The copper ion-doped ZIF-8 shell is degraded in the uniquely acidic microenvironment of inflamed joints, with 95.56 % releasing of Cu(II)Ce6 at pH 6.5. Dynamically limited Cu(II)Ce6 restores dynamic properties when Cu(II)Ce6 reacts with cysteine overexpressed at inflamed joints to generate Cu(I)Ce6. The loaded BSA-MnO2 nanoparticles are able to react with hydrogen peroxide to generate oxygen under acidic conditions, providing a source of oxygen to enhance sonodynamic therapy. Cu2+ released from the decomposition of ZIF-8 nanoreactors undergone a Fenton-like reaction with H2O2 and cysteine to produce ·OH for chemodynamic therapy. In the mouse model of collagen-induced arthritis, the BMCC presents an effective inhibitory effect and excellent biosecurity on rheumatoid arthritis. These results indicate that the BMCC with inflammatory microenvironment-responsive "double-insurance" mechanism possesses a very high biosafety and offers a promising prospect for accurate and efficient treatment of rheumatoid arthritis.