An ATP7A‐Mediated Endogenous Regulation Bio‐Clay Enzyme Enables Self‐Amplified Copper Accumulation for Immunogenic Pyrop

Abstract

ABSTRACT Tumor cells maintain abnormal metabolism to support their rapid proliferation, which often compromises the therapeutic outcomes, including pyroptosis. 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‐amplifying bio‐clay enzyme (Bio‐Clayzyme), 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‐mediated 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‐band center and strengthens tumor cell adhesion, thereby boosting the multi‐enzyme‐like catalytic activity and enabling efficient utilization of short‐lived ROS. Consequently, CuPB/Mt activates nucleotide‐binding oligomerization domain‐like receptor family pyrin domain‐containing 3 (NLRP3)‐dependent pyroptosis and elicits a potent anti‐tumor immune response, offering an ATP7A‐mediated endogenous regulatory paradigm for self‐amplified catalytic therapy and immunogenic pyroptosis.