Nanoengineering Radiotherapy-Evoked Extracellular Vesicles as Personalized Antigen Nanocarriers Facilitate Immune Activation

Abstract Radiotherapy (RT) remains a cornerstone in cancer treatment, yet its immunogenic potential is not fully harnessed for personalized immunotherapy. Here, we report that extracellular vesicles released after radiotherapy (REVs) encapsulate tumor-specific antigens reflective of individual tumor profiles, thereby enabling them to serve as potential personalized antigen repositories. We found that REVs were enriched with immune-related proteins, particularly those involved in antigen processing and presentation. Leveraging this immunostimulatory capacity, we constructed a personalized antigen nanocarrier by surface-engineering these REVs with a thin iron hydroxide coating (REVs@FeOOH). This nanocarrier, which functions as a personalized cancer vaccine, efficiently disrupted the acidic endosomal environment in dendritic cells (DCs), promoting antigen escape into the cytosol and facilitating cross-presentation. Concurrently, the FeOOH layer catalyzed the generation of reactive oxygen species via a Fenton-like catalytic reaction, further driving DC maturation. REVs@FeOOH activated robust antitumor T cell responses and remodeled the immunosuppressive tumor microenvironment. This nanoengineering strategy provides a cost-effective and personalized platform for cancer immunotherapy, with translational potential in breast cancer and other solid tumors.