Engineering tumor-specific catalytic nanosystem for NIR-II photothermal-augmented and synergistic starvation/chemodynamic nanotherapy

BACKGROUND: As an emerging therapeutic modality, chemodynamic therapy (CDT), converting hydrogen peroxide (H(2)O(2)) into highly toxic reactive oxygen species (ROS), has been developed for tumor-specific therapy. However, the deficiency of endogenous H(2)O(2) and high concentration of glutathione (GSH) in the tumor microenvironment (TME) weaken the CDT-based tumor-therapeutic efficacy. Herein, a photothermal-enhanced tumor-specific cascade catalytic nanosystem has been constructed on the basis of glucose oxidase (GOD)-functionalized molybdenum (Mo)-based polyoxometalate (POM) nanoclusters, termed as GOD@POMs. METHODS: GOD@POMs were synthesized by a facile one-pot procedure and covalently conjugation. Then, its structure was characterized by scanning electron microscope (SEM), transmission electron microscope (TEM), Fourier transform infrared (FTIR) spectroscopy and X-ray photoelectron spectroscopy (XPS). In addition, ultraviolet-visible-near-infrared (UV-vis-NIR) absorption spectrum and infrared thermal camera were applied to evaluate the catalytic and photothermal performance, respectively. Moreover, to confirm the therapeutic effects in vitro, cell counting kit-8 (CCK-8) assay, live/dead staining and ROS staining were performed. Furthermore, the biosafety of GOD@POMs was investigated via blood routine, blood biochemistry and hematoxylin and eosin (H&E) staining in Kunming mice. Besides, the C6 glioma tumor-bearing mice were constructed to evaluate its anti-tumor effects in vivo and its photoacoustic (PA) imaging capability. Notably, RNA sequencing, H&E, TdT-mediated dUTP nick end labeling (TUNEL) and Ki-67 staining were also conducted to disclose its underlying anti-tumor mechanism. RESULTS: In this multifunctional nanosystem, GOD can effectively catalyze the oxidation of intratumoral glucose into gluconic acid and H(2)O(2), achieving the cancer starvation therapy. Meanwhile, the generated gluconic acid decreases the pH in TME resulting in POM aggregation, which enables PA imaging-guided tumor-specific photothermal therapy (PTT), especially in the second near-infrared (NIR-II) biological window. Importantly, the Mo (VI) sites on POM can be reduced to Mo (V) active sites in accompany with GSH depletion, and then the post-produced Mo (V) transforms in situ overproduced H(2)O(2) into singlet oxygen ((1)O(2)) via Russell mechanism, achieving self-enhanced CDT. Moreover, the PTT-triggered local tumor temperature elevation augments the synergistic nanocatalytic-therapeutic efficacy. CONCLUSIONS: Consequently, the integration of GOD-induced starvation therapy, H(2)O(2) self-supply/GSH-depletion enhanced Mo-based CDT, and POM aggregation-mediated PTT endow the GOD@POMs with remarkable synergistic anticancer outcomes with neglectable adverse effects. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40824-022-00317-y.