A Sonodynamic Dual‐Prodrug Semiconducting Nanoactivator Inducing Synergistic Ferroptosis‐Pyroptosis Cascade for Enhanced Glioblastoma Therapy

ABSTRACT Glioblastoma (GBM) remains refractory to conventional therapy due to its highly invasive phenotype, intrinsic intratumoral heterogeneity, and the formidable obstacle presented by the blood‐brain barrier (BBB) to effective drug delivery. In this study, we report a sonodynamic dual‐prodrug semiconducting nanoactivator (SPN FeD @Ang), inducing a synergistic ferroptosis‐pyroptosis cascade for enhanced orthotopic GBM therapy. Semiconducting polymer nanoparticles (SPNs) serve as the sonosensitizer cores, generating reactive oxygen species (ROS) upon ultrasound (US) irradiation to initiate prodrug activation. Ferrocene prodrug and pyroptosis prodrug are co‐incorporated into SPNs to enable the induction of ferroptosis and pyroptosis, respectively. The nanoactivators are further surface‐functionalized with angiopep‐2 (Ang) to promote BBB penetration and accumulation in tumors. Upon US stimulation, both prodrugs undergo on‐demand activation, ensuring that these cell‐death pathways are activated within the orthotopic tumor microenvironment. Ferroptosis further enhances pyroptosis activity, inducing a cascading amplification effect on the treatment of GBM. Additionally, it contributes to the activation of antitumor immune responses via the induction of immunogenic cell death (ICD) and the infiltration of immune T cells. In orthotopic GBM models, SPN FeD @Ang + US treatment significantly inhibits tumor growth and maintains 100% survival of treated mice. Thus, this sono‐activatable dual‐prodrug nanoactivator enables on‐demand prodrug activation and establishes a synergistic ferroptosis‐pyroptosis therapeutic strategy.