ROS-autocatalytic nanoplatform interfering astrocyte-cancer crosstalk and enhancing glioblastoma therapy

Abstract Glioblastoma (GBM) remains incurable and exhibits exceptionally high metabolic demands, driving the evolution of hyperactive mitochondrial systems within tumors. In parallel, mitochondrial transfer from astrocytes to cancer cells fuels metabolic reprogramming and enhances GBM tumorigenicity. These malignant traits markedly constrain therapeutic efficacy and patient survival. Herein, we report a dehydroascorbic acid (DHA)-functionalized, ROS-responsive, ferrocene-integrated polymer nanoplatform (GS@DFP) co-loaded with S-Gboxin and Galunisertib, simultaneously targeting GBM mitochondria and mitochondrial transfer in astrocyte-cancer cell crosstalk. After crossing the blood-brain barrier (BBB) through Glut1-mediated transport enabled by DHA, GS@DFP responds to elevated intracellular reactive oxygen species (ROS) levels in GBM to trigger payload release and initiate Fenton reactions. S-Gboxin inhibits mitochondrial complex V and depletes ATP, whereas Galunisertib downregulates TGF-β/SMAD-driven thrombospondin-1 (TSP-1) expression, suppressing tumor microtube (MT) formation and thereby reducing astrocyte-to-GBM mitochondrial transfer. Notably, TGF-β inhibition also reprograms the immunosuppressive tumor microenvironment (TME). This work establishes a multifunctional nanoplatform that targets mitochondrial vulnerabilities and intercellular crosstalk, offering a translatable strategy for enhancing GBM therapy.