Radiotherapy-Potentiated Oncolytic Virotherapy via Iron-Based Metal Organic Framework with Enhanced Ferroptosis

Oncolytic viruses (OVs) represent a promising approach for cancer therapy, but their clinical efficacy is often hindered by pre-existing antiviral immunity and tumor drug resistance. To overcome these obstacles, we developed an iron-based metal–organic framework (MOF Fe ) nanoplatform for OV delivery, which not only protects the virus from neutralizing antibodies in circulation but also enhances intratumoral virus spread through radiation therapy (RT)-induced ferroptosis. The MOF Fe -OV complex (MOF Fe @OV) demonstrated prolonged circulation, enabling it to infect cancer cells without being cleared systemically. Notably, RT in combination with MOF Fe @OV induces iron-dependent ferroptosis, which not only directly kills tumor cells but also increases tumor cell susceptibility to the OVs. In xenograft models of esophageal cancer, MOF Fe @OV + RT achieved significant tumor regression (70.2% volume reduction compared to the control group). Mechanistically, the combined therapy triggered strong ferroptosis in tumor cells via the reduction expression of GPX4 by 65.7%. This study established MOF Fe @OV + RT as a multifunctional platform that integrates viral therapy, ferroptosis induction, and radiosensitization to overcome biological barriers in OV delivery, thereby offering a clinically translatable strategy for enhanced tumor lysis.