Single-atom-doped piezocatalyst induces copper-free cuproptosis in tumor therapy.

Cuproptosis, a distinct cell death pathway, has been integrated into nanomedicine for disease theranostics. However, current nanosystems inducing cuproptosis rely on exogenous toxic copper ions, limiting the scope of biomaterials. Developing nanoplatforms that induce cuproptosis without exogenous copper holds substantial promise. Here, we engineered a two-dimensional iron (Fe) single-atom-doped molybdenum disulfide (MoS) piezocatalyst (Fe-MoS) for tumor therapy. Incorporating single Fe atoms enhances MoS piezoelectric polarization via charge redistribution and modulates Fe and Mo oxidation states, enabling multifaceted enzymatic activities, including peroxidase-, glutathione oxidase-, oxidase-, and catalase-like activities. Upon ultrasound stimulation, the Fe-MoS nanocatalyst generates reactive oxygen species and depletes glutathione via synergistic piezocatalytic and enzyocatalytic effects, disrupting copper ion homeostasis and inducing cuproptosis, concurrently triggering ferroptosis and ferritinophagy, which collectively enhances tumor suppression. This study represents the first paradigm to introduce a copper-free piezocatalyst for initiating cuproptosis, substantially advancing the applications of cuproptosis in tumor therapy.