Intracellular Mutual Promotion of Redox Homeostasis Regulation and Iron Metabolism Disruption for Enduring Chemodynamic Therapy

Intracellular redox homeostasis and the iron metabolism system in tumor cells are closely associated with the limited efficacy of chemodynamic therapy (CDT). Despite extensive attempts, maintaining high levels of intracellular catalysts (free iron) and reactants (H2O2) while decreasing the content of reactive oxygen species (ROS) scavengers (especially glutathione (GSH)) for enduring CDT still remains great challenges. Herein, SS bond‐rich dendritic mesoporous organic silica nanoparticles (DMON) are utilized as GSH‐depleting agents. After co‐loading Fe0 and a catalase inhibitor (3‐amino‐1,2,4‐triazole (AT)), a novel biodegradable nanocarrier is constructed as DMON@Fe0/AT. In the mildly acidic tumor microenvironment, on‐demand ferrous ions and AT are intelligently released. AT suppresses the activity of catalase for H2O2 hoarding, and the exposed DMON weakens ROS scavenging systems by persistently depleting intracellular GSH. The highly efficient •OH production by DMON@Fe0/AT can effectively attack mitochondria and downregulate the expression of ferroportin 1, which can disrupt the cellular iron metabolism system, leading to the desired retention of iron in the cytoplasm. More importantly, DMON@Fe0/AT exhibits a much more efficient CDT killing effect on 4T1 tumor cells than plain Fe0 nanoparticles, benefiting from their synergistic redox regulation and iron metabolism disruption. Overall, the as‐prepared intelligent, degradable DMON@Fe0/AT provides an innovative strategy for enduring CDT. Iron (Fe0) and catalase inhibitor (3‐amino‐1,2,4‐triazole, AT) co‐loaded S‐S bond‐rich dendritic mesoporous organic silica nanoparticles (DMON@Fe0/AT) can increase the production of hydroxyl radicals (•OH) through the regulation of intracellular redox homeostasis. The highly active •OH can effectively damage the structure and function of the mitochondria, reducing the utilization and effusion of free iron ions.