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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\u2010responsive 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\u2010atom copper nanozyme (CuSAE) that implements a \u201cpre\u2010depletion and storm amplification\u201d 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\u2010killing efficacy and robust therapeutic outcomes, establishing itself as a versatile platform that enhances anticancer effects through simultaneous activation of ferroptosis and cuproptosis.<\/jats:p>","DOI":"10.1002\/smll.202514512","type":"journal-article","created":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T09:38:13Z","timestamp":1778837893000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Breaking the \u201cWhack\u2010a\u2010Mole\u201d Dilemma in Cancer Therapy: Ultrasound\u2010Propelled ROS Storm Enables Triple\u2010Modal Cell Death"],"prefix":"10.1002","volume":"22","author":[{"given":"Menglin","family":"Luo","sequence":"first","affiliation":[{"name":"Department of Ultrasound Affiliated Hospital of North Sichuan Medical College  Nanchong 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