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Nanomaterials with shifting or mixed redox states is one of the most common studied nanozyme with peroxidase-like activity for chemodynamic therapy (CDT), which can decompose hydrogen peroxide (H 2 O 2 ) of tumor microenvironment into highly toxic reactive oxygen species (ROS) by a nano-catalytic way. However, most of them exhibit an insufficient catalytic efficiency due to their dependence on catalytic condition. Herein, a potential methodology is proposed to enhance their enzymatic activity by accelerating the redox cycling of these nanomaterials with shifting or mixed redox states in the presence of X-ray. In this study, the nanocomposite consisting of SnS 2 nanoplates and Fe 3 O 4 quantum dots with shifting or mixed redox states (Fe 2+ /Fe 3+ ) is used to explore the strategy. Under external X-ray irradiation, SnS 2 cofactor as electron donor can be triggered to transfer electrons to Fe 3 O 4 , which promotes the regeneration of Fe 2+ sites on the surface of the Fe 3 O 4 . Consequently, the regenerated Fe 2+ sites react with the overexpressed H 2 O 2 to persistently generate ROS for enhanced tumor therapy. The designed nanocomposite displays the synergistic effects of radiotherapy and CDT. The strategy provides a new avenue for the development of artificial nanozymes with shifting or mixed redox states in precise cancer treatments based on X-ray-enhanced enzymatic efficacy., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Development of an efficient nanoradiosensitization system that enhances the radiation doses in cancer cells to sensitize radiotherapy (RT) while sparing normal tissues is highly desirable. Here, we construct a tumor microenvironment (TME)-responsive disassembled small-on-large molybdenum disulfide/hafnium dioxide (MoS 2 /HfO 2 ) dextran (M/H-D) nanoradiosensitizer. The M/H-D can degrade and release the HfO 2 nanoparticles (NPs) in TME to enhance tumor penetration of the HfO 2 NPs upon near-infrared (NIR) exposure, which can solve the bottleneck of insufficient internalization of the HfO 2 NPs. Simultaneously, the NIR photothermal therapy increased peroxidase-like catalytic efficiency of the M/H-D nanoradiosensitizer in TME, which selectively catalyzed intratumorally overexpressed H 2 O 2 into highly oxidized hydroxyl radicals (·OH). The heat induced by PTT also relieved the intratumoral hypoxia to sensitize RT. Consequently, this TME-responsive precise nanoradiosensitization achieved improved irradiation effectiveness, potent oxygenation in tumor, and efficient suppression to tumor, which can be real-time monitored by computed tomography and photoacoustic imaging.

Radiotherapy (RT) in practical use often suffers from off-target side effects and ineffectiveness against hypoxic tumor microenvironment (TME) as well as remote metastases. With regard to these problems, herein, we provide semiconductor heterojunction structured WO 2.9 -WSe 2 -PEG nanoparticles to realize a synergistic RT/photothermal therapy (PTT)/checkpoint blockade immunotherapy (CBT) for enhanced antitumor and antimetastatic effect. Based on the heterojunction structured nanoparticle with high Z element, the nanosystem could realize non-oxygen-dependent reactive oxygen species generation by catalyzing highly expressed H 2 O 2 in TME upon X-ray irradiation, which could further induce immunogenic cell death. Meanwhile, this nanosystem could also induce hyperthermia upon near-infrared irradiation to enhance RT outcome. With the addition of anti-PD-L1 antibody-based CBT, our results give potent evidence that local RT/PTT upon mild temperature and low radiation dose could efficiently ablate local tumors and inhibit tumor metastasis as well as prevent tumor rechallenge. Our study provides not only one kind of radiosensitizer based on semiconductor nanoparticles but also a versatile nanoplatform for simultaneous triple-combined therapy (RT/PTT/CBT) for treating both local and metastasis tumors.

The radioresistance of tumor cells is considered to be an Achilles' heel of cancer radiotherapy. Thus, an effective and biosafe radiosensitizer is highly desired but hitherto remains a big challenge. With the rapid progress of nanomedicine, multifunctional inorganic nanoradiosensitizers offer a new route to overcome the radioresistance and enhance the efficacy of radiotherapy. Herein, poly(vinylpyrrolidone) (PVP)-modified Bi 2 WO 6 nanoplates with good biocompatibility were synthesized through a simple hydrothermal process and applied as a radiosensitizer for the enhancement of radiotherapy for the first time. On the one hand, the high- Z elements Bi ( Z = 83) and W ( Z = 74) endow PVP-Bi 2 WO 6 with better X-ray energy deposition performance and thus enhance radiation-induced DNA damages. On the other hand, Bi 2 WO 6 semiconductors exhibit significant photocurrent and photocatalytic-like radiocatalytic activity under X-ray irradiation, giving rise to the effective separation of electron/hole (e - /h + ) pairs and subsequently promoting the generation of cytotoxic reactive oxygen species, especially hydroxyl radicals ( • OH). The γ-H2AX and clonogenic assays demonstrated that PVP-Bi 2 WO 6 could efficiently increase cellular DNA damages and colony formations under X-ray irradiation. These versatile features endowed PVP-Bi 2 WO 6 nanoplates with enhanced radiotherapy efficacy in animal models. In addition, Bi 2 WO 6 nanoplates can also serve as good X-ray computed tomography imaging contrast agents. Our findings provide an alternative nanotechnology strategy for tumor radiosensitization through simultaneous radiation energy deposition and radiocatalysis.