ROS-Responsive Nanoplatform Targeting Glioblastoma Mitochondrial Crosstalk

Glioblastoma (GBM) remains one of the most lethal brain cancers, largely due to its hyperactive mitochondrial metabolism and its ability to hijack astrocytic mitochondria through tumor microtubes (MTs). This study introduces a multifunctional nanoplatform — GS@DFP, a dehydroascorbic acid (DHA)-functionalized, ferrocene-integrated polymer system — designed to cross the blood-brain barrier (BBB) via Glut1-mediated transport. Once inside GBM cells, the nanoplatform leverages elevated reactive oxygen species (ROS) to trigger controlled drug release and initiate Fenton reactions, amplifying oxidative stress. Dual Payload Strategy - S-Gboxin inhibits mitochondrial complex V, collapsing ATP production and crippling tumor bioenergetics. - Galunisertib blocks TGF-β/SMAD signaling, reducing thrombospondin-1 (TSP-1) expression and suppressing MT formation, thereby limiting astrocyte-to-GBM mitochondrial transfer. Beyond metabolic disruption, Galunisertib also remodels the tumor microenvironment (TME) by alleviating immunosuppression, enhancing the potential for immune-mediated clearance. Why It Matters Together, these mechanisms converge to dismantle GBM’s metabolic resilience and intercellular support systems. By integrating BBB penetration, ROS-responsiveness, and dual-pathway inhibition, GS@DFP represents a multifunctional approach to overcoming resistance mechanisms in glioblastoma therapy.