Disrupting Intracellular Iron Homeostasis by Engineered Metal‐Organic Framework for Nanocatalytic Tumor Therapy in Synergy with Autophagy Amplification‐Promoted Ferroptosis

Abstract Metal‐organic frameworks (MOFs) featuring good biocompatibility and tunable microstructures are developed to generate reactive oxygen species (ROS) for nanocatalytic therapy. However, the relatively low catalytic activity of MOF and intracellular ion homeostasis, a self‐protective mechanism to resist the intracellular accumulation of metal ions, results in the undesirable efficacy of tumor therapy. Herein, a therapeutic strategy is introduced of breaking intracellular iron homeostasis for nanocatalytic therapy in synergy with autophagy amplification‐promoted ferroptosis, based on etched MOF nanocatalyst (denoted COS@MOF), which is self‐etched by thiamine pyrophosphate (TPP) and further modified with autophagy agonist chitosan oligosaccharides (COS). Such self‐etched MOF exhibit an open cavity structure that is more conducive to adsorbing reactive molecules and producing more active sites, and an enhanced Fe(II)/Fe(III) ratio, reinforcing catalytic activity for ROS generation. The catalytic process of COS@MOF can be accelerated by overexpressed endogenous hydrogen sulfide (H₂S) within colorectal tumors which reduces Fe³⁺ into more active Fe²⁺. In vitro and in vivo results demonstrate that COS@MOF amplifies autophagy to break iron homeostasis for facilitating ROS production to promote ferroptosis, achieving synergetic nanocatalytic/ferroptosis tumor therapy. This study provides a promising paradigm to elevate MOF‐based catalytic performance in synergy with autophagy amplification‐promoted ferroptosis for enhanced therapeutic efficacy.