A Stepwise-Confined Self-Reduction Strategy to Construct a Dynamic Nanocatalyst for Boosting Tumor Catalytic Therapy

Fenton/Fenton-like reactions involve the transformation of hydrogen peroxide to hydroxyl radicals to kill tumors. However, the current Fenton/Fenton-like biocatalyst always suffers from low therapeutic efficacy owing to the slow reaction rate of low-valence metal/high-valence metal cycles. Herein, a "stepwise-confined self-reduction" strategy is proposed to construct a dynamic self-reduction dual-metal (Cu/Fe) nanocatalyst in the thiols/disulfide bonds-doped micellar-organosilica framework. The preferential self-reduction of Fe and Cu sources by thiol groups and the dynamic reduction reaction between them in the confined framework produce low-valence and highly active Fe2+ and Cu+ sites in the bimetallic Cu/Fe nanoclusters. The responsively synergistic catalysis of the dual-metal nanocatalyst to generate reactive oxygen species in an acidic and reductive tumor microenvironment is evaluated. Furthermore, the cascade catalysis-induced ferroptosis mechanism through the downregulation of glutathione and glutathione peroxidase 4 protein levels and the overload of Fe2+ is also studied. The in vitro and animal experiments demonstrate that the synergistic catalysis can significantly inhibit tumor growth while ensuring the safety of treatment. This work provides a versatile pathway for the precise construction of bioapplicable multimetal-based nanocatalysts for efficient and safe diagnosis and treatment of tumors.