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: to catalyze the Fenton reaction, leading to DNA damage and glutathione (GSH) depletion. Meanwhile, RSL3 and BQR inhibit the GPX4 and DHODH pathways, respectively, blocking multiple ferroptosis defense targets and thereby inducing robust ferroptosis. PRBP demonstrates favorable T1-weighted magnetic resonance imaging performance, significantly inhibits tumor cell proliferation in vitro, effectively suppresses 4T1 tumor growth in vivo, and exhibits good biosafety. Conclusion: PRBP induces ferroptosis through multiple targets, providing a potent strategy to overcome radiotherapy resistance.