Hydrogen sulfide-generating semiconducting polymer nanoparticles for amplified radiodynamic–ferroptosis therapy of orthotopic glioblastoma

A variety of therapeutic strategies are available to treat glioblastoma (GBM), but the tumor remains one of the deadliest due to its aggressive invasiveness, restrictive blood-brain barrier (BBB), and exceptional resistance to drugs. In this study, we present a hydrogen sulfide (H₂S)-generating semiconducting polymer nanoparticle (PFeD@Ang) for amplified radiodynamic-ferroptosis therapy of orthotopic glioblastoma. Our results show that in an acidic tumor microenvironment (TME), H₂S donors produce large amounts of H₂S, which inhibits mitochondrial respiration and alleviates cellular hypoxia, thus enhancing the radiodynamic effect during X-ray irradiation; meanwhile, Fe³⁺ is reduced to Fe²⁺ by tannic acid in an acidic TME, which promotes an iron-dependent cell death process in tumors. H₂S facilitates the ferroptosis process by increasing the local H₂O₂ concentration <i>via</i> inhibiting catalase activity. This kind of amplified radiodynamic-ferroptosis therapeutic strategy could remarkably inhibit glioma progression in an orthotopic GBM mouse model. Our study demonstrates the potential of PFeD@Ang for GBM treatment <i>via</i> targeted delivery and combinational therapeutic actions of RDT and ferroptosis therapy.