Tumor microenvironment-activated single-atom platinum nanozyme with H(2)O(2) self-supplement and O(2)-evolving for tumor-specific cascade catalysis chemodynamic and chemoradiotherapy

Nanozyme-based tumor collaborative catalytic therapy has attracted a great deal of attention in recent years. However, their cooperative outcome remains a great challenge due to the unique characteristics of tumor microenvironment (TME), such as insufficient endogenous hydrogen peroxide (H(2)O(2)) level, hypoxia, and overexpressed intracellular glutathione (GSH). Methods: Herein, a TME-activated atomic-level engineered PtN(4)C single-atom nanozyme (PtN(4)C-SAzyme) is fabricated to induce the “butterfly effect” of reactive oxygen species (ROS) through facilitating intracellular H(2)O(2) cycle accumulation and GSH deprivation as well as X-ray deposition for ROS-involving CDT and O(2)-dependent chemoradiotherapy. Results: In the paradigm, the SAzyme could boost substantial ∙OH generation by their admirable peroxidase-like activity as well as X-ray deposition capacity. Simultaneously, O(2) self-sufficiency, GSH elimination and elevated Pt(2+) release can be achieved through the self-cyclic valence alteration of Pt (IV) and Pt (II) for alleviating tumor hypoxia, overwhelming the anti-oxidation defense effect and overcoming drug-resistance. More importantly, the PtN(4)C-SAzyme could also convert O(2)(·-) into H(2)O(2) by their superior superoxide dismutase-like activity and achieve the sustainable replenishment of endogenous H(2)O(2), and H(2)O(2) can further react with the PtN(4)C-SAzyme for realizing the cyclic accumulation of ∙OH and O(2) at tumor site, thereby generating a “key” to unlock the multi enzymes-like properties of SAzymes for tumor-specific self-reinforcing CDT and chemoradiotherapy. Conclusions: This work not only provides a promising TME-activated SAzyme-based paradigm with H(2)O(2) self-supplement and O(2)-evolving capacity for intensive CDT and chemoradiotherapy but also opens new horizons for the construction and tumor catalytic therapy of other SAzymes.