Dual-doped metalloporphyrin MOFs-based nanoagent increases low-dose radiotherapy efficacy by apoptosis-ferroptosis for hepatocellular carcinoma

Radiotherapy (RT) represents a cornerstone therapeutic approach in clinical practice for locally control of hepatocellular carcinoma (HCC). However, its efficacy in treating liver cancer is significantly hampered by radiation resistance, which attributed to the insufficient reactive oxygen species (ROS) generation within the tumor microenvironment (TME). To augment RT efficacy, we have developed a novel radiosensitizer termed PTFM. The compound has the features of meso -tetra (4-carboxyphenyl) porphine (TCPP) porphyrin metal–organic frameworks (MOF, PCN-224(Fe)) co-doped with high-atomic element Ta. Under X-ray excitation, the porous PTFM acts as a proficient radio-sensitization, absorbs X-ray energy to promote hydroxyl radicals generation for RT, thereby disrupting the redox balance and intensifying the cytotoxic effect on tumor cells. The incorporation of Fe 3+ into the macrocycle of TCPP within the MOFs shell, facilitates the reactions with GSH and H 2 O 2 in the TME, leads to ROS production that promotes ferroptosis and apoptosis, while also releases O 2 to alleviate tumor hypoxia. Furthermore, PTFM with thermo-metal serves as a dual-mode MR/CT imaging contrast agent, enabling precise RT monitoring and imaging guidance. In conclusion, the radiosensitizer we developed integrates dual-mode imaging capabilities and enhances RT sensitization for HCC through ROS-induced cell apoptosis and ferroptosis, thereby ameliorating tumor hypoxia.