A Responsive Hydrogel Containing Bimetallic MOF Enabling Amplified Ferroptosis for Cancer Therapy via Dual Cellular Homeostasis Disruption

Abstract Ferroptosis, an iron‐dependent form of regulated cell death driven by lipid peroxidation, presents a promising approach for cancer therapy. However, the robust antioxidant defenses of tumor cells and the tightly regulated intracellular iron homeostasis often limit its therapeutic efficacy. A dual cellular homeostasis disruption strategy is proposed herein to amplify ferroptosis for tumor therapy, achieved by a pH/ROS dual‐responsive hydrogel containing a nanoscale bimetallic metal–organic framework (NMOF), (namely Fe‐TCPP(Cu)‐HA), and autophagy inducer chitosan oligosaccharides (COS) inside. Upon exposure to the tumor microenvironment, COS is released from the hydrogel to induce ferritinophagy, disrupting autophagic homeostasis and releasing Fe 2+ . Meanwhile, reactive oxygen species (ROS) generated by the nanocatalytic reaction involving Fe‐TCPP(Cu)‐HA disrupt mitochondrial function, downregulate ferroportin (FPN1), and impair iron export, collectively overwhelming intracellular iron homeostasis. More importantly, Fe‐TCPP(Cu)‐HA in synergy with COS can activate the p53 signal pathway, thus disturb SLC7A11‐GSH‐GPX4 signaling axis, thereby destroying redox homeostasis, and ultimately amplifying ferroptosis. This coordinated dual homeostasis disruptions induces a robust ferroptotic response confirmed by both in vitro and in vivo models, which offers a promising approach for overcoming the limitations of ferroptosis‐based cancer therapy, offering a potential avenue for tumor eradication.