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The emergence of X-ray-induced photodynamic therapy (X-PDT) holds tremendous promise for clinical deep-penetrating cancer therapy. However, the clinical application of X-PDT in cancer treatment is still limited due to the hypoxic property of cancerous tissue, the inherent antioxidant system of tumor cells, and the difficulty in matching the absorption spectra of photosensitizers. Herein, a versatile core-shell radiosensitizer (SCNPs@DMSN@CeO

Recently, various metal peroxide nanomaterials have drawn increasing attention as an efficient hydrogen peroxide (H

Immune checkpoint blockade (ICB) therapy has attracted widespread attention in cancer treatment. Due to the low immunogenicity and immune suppression state in the tumor microenvironment (TME), the therapeutic effects are only moderate. Herein, a TME-activable manganese-boosted catalytic immunotherapy is designed for synergism with ICB therapy to kill tumors efficiently. The tumor cell membrane (CM)-wrapping multienzyme-mimic manganese oxide (MnO

Nanosystem-mediated tumor radiosensitization strategy combining the features of X-ray with infinite penetration depth and high atomic number elements shows considerable application potential in clinical cancer therapy. However, it is difficult to achieve satisfactory anticancer efficacy using clinical radiotherapy for the majority of solid tumors due to the restrictions brought about by the tumor hypoxia, insufficient DNA damage, and rapid DNA repair during and after treatment. Inspired by the complementary advantages of nitric oxide (NO) and X-ray-induced photodynamic therapy, we herein report a two-dimensional nanoplatform by the integration of the NO donor-modified LiYF4:Ce scintillator and graphitic carbon nitride nanosheets for on-demand generation of highly cytotoxic peroxynitrite (ONOO–). By simply adjusting the Ce3+ doping content, the obtained nanoscintillator can realize high radioluminescence, activating photosensitive materials to simultaneously generate NO and superoxide radical for the formation of ONOO– in the tumor. Obtained ONOO– effectively amplifies therapeutic efficacy of radiotherapy by directly inducing mitochondrial and DNA damage, overcoming hypoxia-associated radiation resistance. The level of glutamine synthetase (GS) is downregulated by ONOO–, and the inhibition of GS delays DNA damage repair, further enhancing radiosensitivity. This work establishes a combinatorial strategy of ONOO– to overcome the major limitations of radiotherapy and provides insightful guidance to clinical radiotherapy. Agency for Science, Technology and Research (A*STAR) Submitted/Accepted version Financial support from the National Natural Science Foundation of China (51972075, 51972076, and 51772059), the Natural Science Foundation of Shandong Province (ZR2019ZD29), the Natural Science Foundation of Heilongjiang Province (YQ2019E014), the Postdoctoral Scientific Research Developmental Fund (LBH-Q18034), and the Ph.D. Student Research and Innovation Fund of the Fundamental Research Funds for the Central Universities (3072020GIP1016) are greatly acknowledged. This research is also supported by the Singapore Agency for Science, Technology and Research (A*STAR) AME IRG grant (A20E5c0081).

Reactive oxygen species (ROS)-based therapeutic modalities including chemodynamic therapy (CDT) and photodynamic therapy (PDT) hold great promise for conquering malignant tumors. However, these two methods tend to be restricted by the overexpressed glutathione (GSH) and hypoxia in the tumor microenvironment (TME). Here, we develop biodegradable copper/manganese silicate nanosphere (CMSN)-coated lanthanide-doped nanoparticles (LDNPs) for trimodal imaging-guided CDT/PDT synergistic therapy. The tridoped Yb3+/Er3+/Tm3+ in the ultrasmall core and the optimal Yb3+/Ce3+ doping in the shell enable the ultrabright dual-mode upconversion (UC) and downconversion (DC) emissions of LDNPs under near-infrared (NIR) laser excitation. The luminescence in the second near-infrared (NIR-II, 1000-1700 nm) window offers deep-tissue penetration, high spatial resolution, and reduced autofluorescence when used for optical imaging. Significantly, the CMSNs are capable of relieving the hypoxic TME through decomposing H2O2 to produce O2, which can react with the sample to generate 1O2 upon excitation of UC photons (PDT). The GSH-triggered degradation of CMSNs results in the release of Fenton-like Mn2+ and Cu+ ions for •OH generation (CDT); simultaneously, the released Mn2+ ions couple with NIR-II luminescence imaging, computed tomography (CT) imaging, and magnetic resonance (MR) imaging of LDNPs, performing a TME-amplified trimodal effect. In such a nanomedicine, the TME modulation, bimetallic silicate photosensitizer, Fenton-like nanocatalyst, and NIR-II/MR/CT contrast agent were achieved "one for all", thereby realizing highly efficient tumor theranostics.