Three‐in‐One: Biomimetic Trimetallic Ionic‐Site Nanozyme Composite as a Redox Homeostasis Disruptor for Ferroptosis/Cuproptosis/Pyroptosis Co‐Activated Nanocatalytic Therapy

Given the critical role of tumor redox homeostasis in sustaining malignant growth, simultaneously targeting multiple aspects of intracellular balance may offer a more efficient therapeutic strategy. Herein, a trimetallic ionic-site nanozyme is engineered by integrating Au³⁺, Ru³⁺, and Cu²⁺ ions into a nanoscale metal-organic framework (tis-ARC). The nanozyme is further loaded with gambogic acid (GA) and buthionine sulfoximine (BSO) and cloaked in tumor cell membranes (tis-ARC-GB@M) to enhance targeting and homologous recognition. The resulting tis-ARC-GB@M exhibited multi-enzyme mimetic catalytic activities that disrupted tumor redox balance by simultaneously amplifying reactive oxygen species (ROS) production and depleting glutathione (GSH), thereby dismantling the tumor's intrinsic antioxidant defenses. This cascade of events triggered several cell death pathways-including ferroptosis, cuproptosis, and pyroptosis, and released damage-associated biomarker molecules that reprogrammed the tumor microenvironment (TME). Mechanistically, oxidative stress-enhanced ferroptosis, cuproptosis, and pyroptosis collectively disrupted mitochondrial metabolism, which in turn exacerbated intracellular oxidative stress, resulting in a mutually reinforcing therapeutic effect. In vitro and in vivo studies demonstrated that tis-ARC-GB@M significantly suppressed tumor growth in tumor-bearing models. Overall, this approach establishes a novel paradigm for antitumor nanocatalytic therapy through the targeted disruption of intracellular homeostasis.