Chemodynamic therapy (CDT), which converts overexpressed hydrogen peroxide (H2O2) in tumor cells to hydroxyl radicals (& BULL;OH) by Fenton reactions, is considered a prospective strategy in anticancer therapy. However, the high level of glutathione (GSH) and poor Fenton catalytic efficiency contribute to the suboptimal efficiency of CDT. Herein, we present a multifunctional nanoplatform (CuFe2O4@HA) that can induce GSH depletion and combine with photothermal therapy (PTT) to enhance antitumor efficacy. CuFe2O4@HA nanoparticles could release Cu2+ and Fe3+ after entering tumor cells by targeting hyaluronic acid (HA). Subsequently, Cu2+ and Fe3+ were reduced to Cu+ and Fe2+ by GSH, where Cu+/Fe2+ significantly catalyzed H2O2 to produce a higher level of & BULL;OH, and the depletion of GSH disrupted the antioxidant capacity of the tumor. Therefore, depleting GSH substantially enhances the level of & BULL;OH in tumor cells. In addition, CuFe2O4@HA nanoparticles have considerable absorption in the near-infrared (NIR) region, which can stimulate excellent PTT effects. More importantly, the heat generated by PTT can further enhance the Fenton catalysis efficiency. In vitro and in vivo experiments have demonstrated the excellent tumor-killing effect of CuFe2O4@HA nanoparticles. This strategy overcomes the problem of insufficient CDT efficacy caused by GSH overexpression and poor catalytic efficiency. Moreover, this versatile nanoplatform provides a reference for self-enhanced CDT and PTT/CDT synergistic targeted therapy.
