A Multisynergistic Strategy for Bone Tumor Treatment: Orchestrating Oxidative Stress and Autophagic Flux Inhibition by Environmental‐Response Nanoparticle

Abstract Tumor therapy has advanced significantly in recent years, but tumor cells can still evade and survive the treatment through various mechanisms. Notably, tumor cells use autophagy to sustain viability by removing impaired mitochondria and clearing excess reactive oxygen species (ROS). In this study, the aim is to amplify intracellular oxidative stress by inhibiting mitochondrial autophagic flux. Multisynergistic environmental‐response nanoparticles (ERNs) are engineered by integrating gold nanoparticles and copper peroxide with borosilicate bioactive glass. The controlled release of copper and inhibition of autophagy flux triggered an overabundance and accumulation of oxidative stress within the tumor cells. This stress triggered immunogenic tumor cell death, believed to initiate a systemic immune response. The tumor microenvironment (TME) transitioned back to a normal physiological state as tumor cells are ablated. ERNs responded to the microenvironment changes by depositing hydroxyapatite on the surface and spontaneously enhancing bone regeneration. This innovative formulation facilitates the functional transition of ERNs from “anti‐tumor therapy” to “biomineralization” that kills cancers and induces new bone formation. Overall, it is shown that the ERNs effectively eradicate cancers by utilizing chemodynamic therapy, starvation therapy, and immunotherapy.