Diselenide-Bridged Iron-Porphyrin MOF for MRI-Guided Radiotherapy via Triple-Pathway Ferroptosis.

Introduction: Radiation resistance poses a significant challenge in clinical cancer therapy. Ferroptosis, an iron-dependent form of cell death, plays an important role in the efficacy of radiotherapy. However, cancer cells often activate defense systems to survive this process. Moreover, interventions targeting only a single defense pathway often yield limited effects. Methods: To overcome radioresistance, we have developed a reactive oxygen species (ROS)-responsive nanosystem named PRBP. This system employs a siderophore-based framework PCN(Fe) as the core, loaded with two specific drugs: RAS-selective lethal compound 3 (RSL3) to block the glutathione peroxidase 4 (GPX4) pathway, and brequinar (BQR) to inhibit the dihydroorotate dehydrogenase (DHODH) pathway. The surface is coated with a diselenide bond-linked polyethylene glycol (PEG-Se-Se-PEG) layer that dissociates in a ROS-rich environment. Upon X-ray irradiation, the system rapidly degrades and releases the drugs, while iron ions trigger the Fenton reaction. RSL3 and BQR synergistically suppress the ferroptosis defense system, inducing a potent "ferroptosis storm." Through in vitro and in vivo experiments, we systematically evaluated the physical properties, magnetic resonance imaging (MRI) capability, and therapeutic efficacy of this platform. Results: PRBP exhibits a uniform morphology and undergoes responsive degradation under X-ray irradiation, releasing Fe Conclusion: PRBP induces ferroptosis through multiple targets, providing a potent strategy to overcome radiotherapy resistance.