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

Abstract 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 1O2 for RDT. Moreover, by the inhibition of oxidative phosphorylation, the weak acidity and glutathione (GSH)‐responsive release of LND achieves O2 economization, which promotes the generation of ROS and stabilizes DNA damage. Intriguingly, Pt(II)TCPP exhibits the capability of O2 concentration‐dependent near infrared luminescence imaging‐guided RT‐RDT. Moreover, the decomposition of FPTM‐LP under high concentration of GSH generates large amounts of Fe2+, 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.