Fn14-targeting, NIR-II responsive nanomaterials for enhanced radiotherapy against glioblastomas.

Radiotherapy is a common treatment option for patients with glioblastoma multiforme. However, tumor heterogeneity causes varying responses to radiation among different tumor subpopulations. Cancer cells that endure radiotherapy exhibit radioresistance, resulting in the ineffectiveness of radiation therapy and eventual tumor relapse. In this study, we discovered that the fibroblast growth factor-inducible 14 (Fn14)-positive tumor cells were enriched in tumor residual foci after radiation, ultimately leading to treatment failure. Fn14-expressing glioma cells survived ionizing radiation through preferential activation of DNA damage checkpoint response. We have thus engineered an Fn14-targeting and NIR-II responsive plasmonic gold nanosystem named Fn14-AuNPs, which can precisely internalize into Fn14-overexpressed glioma cells and have an excellent BBB-crossing capability. As gold nanoparticles, by inhibition of DNA repair processes and induction of G(2)/M cells cycle arrest, Fn14-AuNPs nanoparticles improved the radiosensitivity of tumor cells. Meanwhile, Fn14-AuNPs induced localized heat under NIR-II photoirradiation, thus impeding RT-induced DNA damage checkpoint response. This versatile nanosensitizer, combined with NIR-II laser photoirradiation, can eradicate radioresistant subpopulations of glioblastoma and improve the therapeutic effect of radiotherapy. This finding presents an effective radiosensitization strategy by targeting radioresistant subpopulations, which can efficiently overcome the constraints imposed in clinical radiotherapy and offer a hopeful avenue to enhance the treatment effectivity of radiotherapy in glioblastoma.