Nanoscale Metal-Organic Framework-Based Self-Monitoring Oxygen Economizer and ROS Amplifier for Enhanced Radiotherapy-Radiodynamic Therapy

Radiotherapy-radiodynamic therapy (RT-RDT) has emerged as a promising approach due to its remarkable anticancer efficacy. However, hypoxic tumor microenvironment and insufficient energy deposition severely reduce the radiotherapy outcomes. Herein, lonidamine (LND)-loaded Fe(III) metal-Pt(II) porphyrin framework (FPTM-LP) is designed for radiosensitization through hypoxia alleviation and reactive oxygen species (ROS) amplification. Specifically, the high-Z element Pt effectively absorbs X-ray photons to generate •OH for RT while transferring X-ray energy to porphyrin (TCPP), which stimulates the generation of 1 O 2 for RDT. Moreover, by the inhibition of oxidative phosphorylation, the weak acidity and glutathione (GSH)-responsive release of LND achieves O 2 economization, which promotes the generation of ROS and stabilizes DNA damage. Intriguingly, Pt(II)TCPP exhibits the capability of O 2 concentration-dependent near infrared luminescence imaging-guided RT-RDT. Moreover, the decomposition of FPTM-LP under high concentration of GSH generates large amounts of Fe 2+ , leading to the augmented production of •OH via Fenton reactions. In brief, this work presents a radiosensitizer with a unique and efficient mechanism of self-monitoring hypoxia alleviation and increasing ROS levels for enhanced cancer RT-RDT. The radiosensitization potency of FPTM-LP is confirmed in tumor-bearing mice in vivo, proclaiming a new strategy for enhancing therapeutic efficacy and minimizing side effects.