Oxygen-Enriched MOF-Hemoglobin X-ray Nanosensitizer for Enhanced Cancer Radio–Radiodynamic Therapy

Radiotherapy-radiodynamic therapy (RT-RDT) has evolved as a transformative strategy to overcome the problem of tumor radioresistance present in conventional radiotherapy. However, the antitumor efficiency of oxygen-dependent RT-RDT remains severely impeded by the hypoxic microenvironment prevalent in solid tumors. Here, we utilized Hf clusters and photosensitive ligands to prepare hierarchical porous metal–organic frameworks (HP-MOFs) with specific pore sizes, which can precisely encapsulate oxygen-carrying hemoglobin to alleviate tumor hypoxia, thus achieving significantly enhanced RT-RDT treatment efficiency. As high Z-metal, Hf clusters in MOF-based nanosensitizers allow for efficient deposition of X-ray energy to improve tumor cell sensitivities. Additionally, they serve as the scintillator to transfer the X-ray energy to photosensitive ligands, sensitizing oxygen to generate singlet oxygen. The incorporation of hemoglobin enables the direct delivery of sufficient oxygen to tumor cells, ameliorating the hypoxic state and potentiating the efficacy of RT-RDT. Both in vivo and in vitro studies have demonstrated the excellent anticancer effect and biocompatibility of the oxygen-enriched MOF-hemoglobin nanosystem under X-ray irradiation. This study constructs a MOF-based X-ray nanosensitizer integrating high-Z elements, photosensitizers, and oxygen-carrying proteins, which can effectively surmount the limitations encountered in clinical radiotherapy and provide a promising new direction for further advancement of RT-RDT.