Tumor microenvironment-activated single-atom platinum nanozyme with H2O2 self-supplement and O2-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 (H2O2) level, hypoxia, and overexpressed intracellular glutathione (GSH). Methods: Herein, a TME-activated atomic-level engineered PtN4C single-atom nanozyme (PtN4C-SAzyme) is fabricated to induce the "butterfly effect" of reactive oxygen species (ROS) through facilitating intracellular H2O2 cycle accumulation and GSH deprivation as well as X-ray deposition for ROS-involving CDT and O2-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, O2 self-sufficiency, GSH elimination and elevated Pt2+ 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 PtN4C-SAzyme could also convert O2·- into H2O2 by their superior superoxide dismutase-like activity and achieve the sustainable replenishment of endogenous H2O2, and H2O2 can further react with the PtN4C-SAzyme for realizing the cyclic accumulation of ∙OH and O2 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 H2O2 self-supplement and O2-evolving capacity for intensive CDT and chemoradiotherapy but also opens new horizons for the construction and tumor catalytic therapy of other SAzymes.