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

Abstract

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 via 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 via targeted delivery and combinational therapeutic actions of RDT and ferroptosis therapy.