Multimode Imaging-Guided Photothermal/Chemodynamic Synergistic Therapy Nanoagent with a Tumor Microenvironment Responded Effect

The development of near-infrared (NIR) laser triggered phototheranostics for multimodal imaging-guided combination therapy is highly desirable. However, multiple laser sources, as well as inadequate therapeutic efficacy, impede the application of phototheranostics. Here, we develop an all-in-one theranostic nanoagent PEGylated DCNP@DMSN-MoOx NPs (DCDMs) with a flower-like structure fabricated by coating uniformly sized down-conversion nanoparticles (DCNPs) with dendritic mesoporous silica (DMSN) and then loading the ultrasmall oxygen-deficient molybdenum oxide nanoparticles (MoOx NPs) inside through an electrostatic interaction. Owing to the doping of Nd ions, when excited by an 808 nm laser, DCNPs emit bright NIR-II emissions (1060 and 1300 nm), which have characteristic high spatial resolution and deep tissue penetration. In terms of treatment, MoOx NPs could be specifically activated by excessive hydrogen peroxide (H2O2) in the tumor microenvironment, thus generating 1O2 via the Russell mechanism. In addition, the excessive glutathione (GSH) in the tumor cells could be depleted through the Mo-mediated redox reaction, thus effectively decreasing the antioxidant capacity of tumor cells. Importantly, the excellent photothermal properties (photothermal conversion efficiency of 51.5% under an 808 nm laser) synergistically accelerate the generation of 1O2. This cyclic redox reaction of molybdenum indeed ensured the high efficacy of tumor-specific therapy, leaving the normal tissues unharmed. MoOx NPs could also efficiently catalyze tumor endogenous H2O2 into a considerable amount of O2 in an acidic tumor microenvironment, thus relieving hypoxia in tumor tissues. Moreover, the computed tomography (CT) and T1-weighted magnetic resonance imaging (MRI) effect from Gd3+ and Y3+ ions make DCNPs act as a hybrid imaging agent, allowing comprehensive analysis of tumor lesions. Both in vitro and in vivo experiments validate that such an "all-in-one" nanoplatform possesses desirable anticancer abilities under single laser source irradiation, benefiting from the NIR-II fluorescence/CT/MR multimodal imaging-guided photothermal/chemodynamic synergistic therapy. Overall, our strategy paves the way to explore other noninvasive cancer phototheranostics.