Multifunctional Iron‐Doped Hollow Mesoporous Silica Nanoregulator for Enhanced Tumor Chemodynamic Therapy

Abstract Chemodynamic therapy (CDT) is a promising method that uses endogenous hydrogen peroxide (H2O2) to produce cytotoxic hydroxyl radicals (•OH) via Fenton reaction to kill tumor cells. However, the insufficient contents of H2O2 and the presence of glutathione (GSH) can significantly reduce the therapeutic effect of CDT. Herein, a multifunctional nanoregulator (3‐AT&MA@FHM) that combines Fe‐doped hollow mesoporous silica nanoparticles (Fe‐doped hMSN, or FHM) with 3‐amino‐1,2,4‐triazole (3‐AT) and maleimide (MA) are developed to overcome these challenges. After endocytosis by tumor cells, FHM part of the nanoregulator degrades in a mildly acidic intracellular environment and releases Fe3+ for CDT. The subsequently released 3‐AT serves as a catalase inhibitor to promote the accumulation of H2O2, while MA acts as a GSH scavenger to decrease the GSH content in tumor cells. This multifunctional nanoplatform simultaneously regulates the contents of H2O2‐the substrate for Fenton reaction and GSH‐the main antioxidant, resulting in a significantly enhanced CDT effect. Moreover, organoids are used for safety and toxicity evaluation. The results of organoids experiments showed similar trends to those of cellular experiments, but MIO is more resistant to stress than cells. This study is expected to provide a novel idea for the design of highly efficient CDT nanosystems.