Structurally Engineered Ferrous Metal-Organic Framework as a Chemodynamic Therapy Nanoagent for Concurrent Hydroxyl...

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 (¹O₂) through the Russell mechanism. However, current nanoplatforms efficiently produce either •OH or ¹O₂, 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 ¹O₂ 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 ¹O₂ 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.