Structurally Engineered Ferrous Metal–Organic Framework as a Chemodynamic Therapy Nanoagent for Concurrent Hydroxyl Radical and Singlet Oxygen Generation

ABSTRACT Chemodynamic therapy (CDT) is an emerging cancer treatment that employs transition metal–based nanoagents to catalyze the conversion of elevated intracellular hydrogen peroxide in malignant cells into cytotoxic hydroxyl radicals (•OH) via Fenton‐like reactions. Recent developments have also introduced CDT agents that generate singlet oxygen ( 1 O 2 ) through the Russell mechanism. However, current nanoplatforms efficiently produce either •OH or 1 O 2 , but not both, and often exhibit suboptimal catalytic activity, thereby limiting the sufficient production of reactive oxygen species (ROS) required for cancer eradication. This report introduces a ferrous metal–organic framework, Fe(II)‐TCPP (tetrakis(4‐carboxyphenyl)porphyrin), as the first nanoagent capable of simultaneously and effectively generating •OH and 1 O 2 through dual catalytic pathways. Its nanoneedle‐like morphology increases the surface area and promotes enhanced ROS production. Cell studies demonstrated selective intracellular generation of •OH and 1 O 2 in cancer cells, resulting in targeted cytotoxicity while sparing non‐malignant cells. Systemic administration of Fe(II)‐TCPP in a breast cancer mouse model resulted in preferential tumor accumulation, robust intratumoral ROS generation, cancer eradication, and prevention of recurrence without systemic toxicity. These findings mark a foundational advance in CDT nanoagents by integrating Fenton and Russell mechanisms into a single platform, enabling the design of multifunctional catalysts with enhanced ROS output and therapeutic efficacy.