Multi‐Signal Responsive Allosteric Nanozymes for Spatiotemporally Confined Ferroptosis via Tumor‐Intrinsic Stress Amplification

Ferroptosis, an iron-dependent form of regulated cell death, holds great promise for eliminating therapy-resistant tumors, but clinical translation has been limited by poor spatiotemporal selectivity and the lack of dynamic control over catalytic activity. Here we present a multi-signal responsive allosteric nanozyme platform that exploits tumor-intrinsic stress amplification (TISA) to achieve spatiotemporally confined ferroptosis. The design integrates three microenvironmental cues-reactive oxygen species (ROS), acidic pH, and elevated glutathione (GSH)-as cooperative allosteric effectors: ROS primes the catalyst, acidic pH accelerates peroxidase-like (POD-like) activity, and intracellular GSH acts as a reversible brake to self-limit activity post-activation. Only upon convergence of all three signals does the nanozyme switch from an off-state to a high-turnover state, triggering localized lipid peroxidation and bypassing systemic oxidative damage. Across orthotopic and metastatic tumor models, TISA nanozymes selectively amplified ferroptotic stress in tumor tissue, overcame antioxidant buffering, and suppressed tumor growth with minimal off-target toxicity. This multi-layered gating and confinement strategy establishes a blueprint for precision ferroptosis nanomedicine and offers a generalizable approach to harness complex tumor microenvironment signals for safe and effective catalytic therapy.