Breaking the “Whack‐a‐Mole” Dilemma in Cancer Therapy: Ultrasound‐Propelled ROS Storm Enables Triple‐Modal Cell Death

ABSTRACT Advances in nanomedicine have enabled precise induction of regulated cell death (RCD) for cancer therapy. While apoptosis remains a therapeutic cornerstone, the recent discovery of ferroptosis and cuproptosis has opened new therapeutic dimensions. However, conventional ferroptosis inducers suffer from limitations such as poor stability and susceptibility to drug resistance. Nanozymes, with their high catalytic activity and tumor microenvironment‐responsive characteristics, offer promising solutions to these challenges. To overcome the limitations of monotherapies often constrained by compensatory pathways and acquired resistance, we rationally designed a sonodynamic single‐atom copper nanozyme (CuSAE) that implements a “pre‐depletion and storm amplification” strategy. This approach generates a decisive reactive oxygen species (ROS) storm that acts as a master trigger to synchronously activate three distinct RCD pathways: apoptosis, ferroptosis, and cuproptosis, thereby providing an innovative solution to combat therapeutic resistance. In mouse models of ovarian cancer, CuSAE demonstrated remarkable tumor‐killing efficacy and robust therapeutic outcomes, establishing itself as a versatile platform that enhances anticancer effects through simultaneous activation of ferroptosis and cuproptosis.