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-MoO_x 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 (MoO_x 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, MoO_x 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. MoO_x 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.