Piezoelectric nanocatalysts disrupt energy metabolism and redox homeostasis for potent tumor eradication

Targeting cancer cell metabolism and redox homeostasis represents a promising therapeutic strategy, yet achieving sustained disruption remains challenging. Herein, we synthesized a piezoelectric-responsive three-dimensional metal-organic framework (MOFs) nanocatalyst (Cu-800@HA) that utilizes ultrasound (US) to initiate a self-enhancing cycle of oxidative stress and energy depletion. Under US stimulation, Cu-800@HA induces piezoelectric catalytic reactions to generate substantial intracellular hydrogen peroxide (H₂O₂), which triggers cupric ion mediated Fenton-like reactions that deplete glutathione (GSH) and initiate ferroptosis. This process leads to mitochondrial damage and ATP depletion, consequently reducing the activity of copper-transporting ATPase 1 (ATP7B) and inducing oligomerization of dihydrolipoamide S-acetyltransferase (DLAT). The diminished enzymatic activity effectively inhibits copper ion efflux, resulting in intracellular copper accumulation that exacerbates cuproptosis. The synergistic interplay between cuproptosis and ferroptosis progressively amplifies intracellular oxidative stress, culminating in extensive tumor cell death. This dual-pathway intervention coordinately disrupts metabolic and redox homeostasis, achieving potent tumor eradication <em>in vivo</em> with minimal systemic toxicity. Our work establishes a novel therapeutic paradigm that couples piezoelectric catalysis with programmed cell death pathways through metabolic disruption, providing a robust strategy for tumor treatment.