Self-disassembling diatomic nanocluster bomb unlock reciprocal synergistic multi-pathway cancer therapy

The emerging chemodynamic therapy (CDT), which leverages tumour microenvironment (TME)-specific conversion of H₂O₂ into cytotoxic reactive oxygen species (ROS), suffers from limited efficacy due to low-level endogenous H₂O₂, inefficient ROS generation, and oxidative stress adaptation. Herein, we develop self-reporting CuFe nanodetonators (CuFe NCs) as 'nanocluster bomb' to integrate multi-pathway therapeutics for enhanced cancer treatment. Such NCs encapsulate oxygen-vacancy-mediated bandgap engineered CuFe peroxides within TME-responsive shells, which triggers controllable release of peroxides into the tumour cells, enabling high-level endogenous H₂O₂. ROS generation is then amplified through the robust and sustained Cu-Fe dual redox cycling and laser-assisted photothermal effect. CuFe NCs enable trimodal therapy and significantly enhance therapeutic efficacy by 198.8%. Moreover, integrated with dihydrorhodamine 123 (DHR123) as a fluorescence self-reporter, the system allows dynamic intracellular ROS monitoring and precise activation of PTT/PDT. In vitro MDA-MB-468 cells and in vivo BALB/c nude mice validations demonstrate that CuFe NCs potentiate anticancer outcomes through downregulation of Fe-S cluster proteins, upregulation of iron metabolism proteins, and elevated ACSL4 protein levels. This study presents a multivalent dual metal ion-mediated bandgap engineering approach to amplify CDT efficacy and highlights the multi-mechanistic potential of CuFe-based nanotherapeutics.