Nanozyme catalyzed cascade reaction for enhanced chemodynamic therapy of low-H2O2 tumor

The efficacy of chemodynamic therapy (CDT) is strongly dependent on the hydrogen peroxide (H2O2) level of tumor tissues. Nanozyme-mediated glycolysis reaction is considered as a promising way to supply the amount of H2O2 in situ, therefore, the development of nanozyme-based CDT platform is desirable for low-H2O2 tumor treatment. Herein, we developed a hybrid nanozyme (denoted as MMF-Au) composed of ultrasmall gold nanoparticles (Au NPs) and melanin-coated manganese dioxide flowers (MMF) for enhanced CDT of low-level H2O2 tumors under the guidance of magnetic resonance imaging (MRI) and photoacoustic imaging (PAI). The MMF-Au nanozyme could trigger the cascade reaction of glucose oxidation and Fenton-like reaction. First, the ultrasmall Au NPs with glucose oxidase (GOx)-mimic activity could catalyze the oxidation of glucose to generate large amount of H2O2. Subsequently, the H2O2 was converted into highly toxic hydroxyl radicals (•OH) via a Mn2+-mediated Fenton-like reaction, due to the release of Mn2+ during the decomposition of MMF in tumor acid microenvironment. Meanwhile, the released Mn2+ could perform T1-weighted MRI. Additionally, the MMF-Au could be used for PAI and photothermal therapy (PTT) due to the strong absorption of melanin in the near-infrared (NIR) region. Both in vitro and in vivo experimental results demonstrated that nanozyme catalyzed cascade reaction could achieve better CDT efficacy in tumors with low level of H2O2. This study provided a promising strategy to construct nanozyme-triggered cascade reaction system against low-level H2O2 tumors.