Space-Selective Chemodynamic Therapy of CuFe₅O₈ Nanocubes for Implant-Related Infections

Implant-related infections (IRIs) are a serious complication after orthopedic surgery, especially when a biofilm develops and establishes physical and chemical barriers protecting bacteria from antibiotics and the hosts local immune system. Effectively eliminating biofilms is essential but difficult, as it requires not only breaking the physical barrier but also changing the chemical barrier that induces an immunosuppressive microenvironment. Herein, tailored to a biofilm microenvironment (BME), we proposed a space-selective chemodynamic therapy (CDT) strategy to combat IRIs using metastable CuFe₅O₈ nanocubes (NCs) as smart Fenton-like reaction catalysts whose activity can be regulated by pH and H₂O₂ concentration. In the biofilm, extracellular DNA (eDNA) was cleaved by high levels of hydroxyl radicals (•OH) catalyzed by CuFe₅O₈ NCs, thereby disrupting the rigid biofilm. Outside the biofilm with relatively higher pH and lower H₂O₂ concentration, lower levels of generated •OH effectively reversed the immunosuppressive microenvironment by inducing pro-inflammatory macrophage polarization. Biofilm fragments and exposed bacteria were then persistently eliminated through the collaboration of pro-inflammatory immunity and •OH. The spatially selective activation of CDT and synergistic immunomodulation exerted excellent effects on the treatment of IRIs in vitro and in vivo. The anti-infection strategy is expected to provide a method to conquer IRIs.