Multifunctional Nanoreactor Based on Catalyst Surface Engineering Combines pH-Adaptive Catalysis With Tumor Microenvironment Modulation for Synergistic Chemodynamic-Chemotherapy.

Abstract

Chemodynamic therapy (CDT) is a novel therapeutic strategy based on the Fenton reaction, which utilizes endogenous hydrogen peroxide (H2O2) to generate toxic hydroxyl radicals (•OH) for killing tumor cells. However, the mildly acidic pH and limited H2O2 levels in the tumor microenvironment (TME) restrict the activity of the Fenton reaction, severely limiting the therapeutic efficacy of CDT. Here, we construct a multifunctional nanoreactor, Fe2O3@MoS2-Pt/FA, which combines catalyst surface engineering with intracellular metabolic regulation to achieve highly efficient synergy between CDT and chemotherapy. This nanoreactor constructs a localized acidic microenvironment by bonding MoS2 onto the surface of Fe2O3, enabling the Fenton catalyst to maintain high catalytic activity under mildly acidic conditions and thereby overcoming the environmental pH limitation. Meanwhile, the introduction of cisplatin precursors containing disulfide bonds enabled glutathione-responsive release. Cisplatin not only exerts its chemotherapeutic effects but also promotes intracellular H2O2 production by activating relevant pathways, providing more abundant substrates for CDT. Through these synergistic multimodal mechanisms, this nanoreactor induces tumor cell apoptosis by causing DNA damage, disrupting cellular redox homeostasis, and impairing mitochondrial and nuclear functions. This study provides an effective nanoplatform design strategy to overcome the limitations of TME pH and H2O2 insufficiency in CDT.