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Inhibiting the copper transporter ATPase (ATP7A) effectively disrupts this metabolic balance, yet current exogenous ATP7A inhibition strategies suffer from poor delivery efficiency and low tumor selectivity. Herein, we developed an endogenous regulation strategy to downregulate ATP7A levels using a self\u2010amplifying bio\u2010clay enzyme (Bio\u2010Clayzyme), cupriferous Prussian blue\/montmorillonite (CuPB\/Mt). Upon tumor cell internalization, CuPB\/Mt induces a robust reactive oxygen species (ROS) storm, accompanied by antioxidant depletion, mitochondrial dysfunction, and adenosine triphosphate (ATP) exhaustion. These metabolic disturbances are associated with reduced ATP7A expression, which may subsequently impair ATP7A\u2010mediated copper efflux. The resulting intracellular copper accumulation may further promote ROS amplification, supporting a positive feedback loop among ROS production, ATP7A downregulation, and copper retention. Specifically, the introduction of Mt optimizes the Cu d\u2010band center and strengthens tumor cell adhesion, thereby boosting the multi\u2010enzyme\u2010like catalytic activity and enabling efficient utilization of short\u2010lived ROS. Consequently, CuPB\/Mt activates nucleotide\u2010binding oligomerization domain\u2010like receptor family pyrin domain\u2010containing 3 (NLRP3)\u2010dependent pyroptosis and elicits a potent anti\u2010tumor immune response, offering an ATP7A\u2010mediated endogenous regulatory paradigm for self\u2010amplified catalytic therapy and immunogenic pyroptosis.<\/jats:p>","DOI":"10.1002\/advs.77973","type":"journal-article","created":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T03:04:45Z","timestamp":1791774285000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["An ATP7A\u2010Mediated Endogenous Regulation Bio\u2010Clay Enzyme Enables Self\u2010Amplified Copper Accumulation for Immunogenic Pyrop"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-3266-1471","authenticated-orcid":false,"given":"Weimin","family":"Xie","sequence":"first","affiliation":[{"name":"Engineering Research Center of 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