GSH-responsive and Mitochondria-targeting Multifunctional Nanoplatform for MR imaging-guided enhanced chemotherapy of Glioma by Reshaping the Tumor Immune Microenvironment

Despite considerable progress in glioma research, present therapeutic approaches continue to be insufficiently efficacious, predominantly owing to challenging hindrances in conveying chemotherapy drugs across the blood-brain barrier (BBB) and reshaping the immunosuppressive tumor microenvironment (TME). In this study, a multifunctional nanoplatform was developed comprising poly-lactide-co-glycolide (PLGA) encapsulated with MnO ₂ nanoparticles, triphenylphosphonium (TPP) conjugated with doxorubicin (DOX), and Angiopep-2 (Ang) for the magnetic resonance imaging-guided enhanced chemotherapy of glioma. The role of Ang promotes BBB penetration and tumor cell targeting, while TPP allows for an increased concentration of the Ang-PMT NPs in the mitochondria. Upon exposure to high concentration of glutathione (GSH) within the TME, the Ang-PMT NPs disintegrate rapidly, resulting in the production of Mn ²⁺ and the subsequent release of DOX. The released DOX directly eradicates tumor cells and catalyzes mitochondrial DNA release, leading to immunogenic cell death (ICD) and the activation of the cGAS-STING pathway. Furthermore, the produced Mn ²⁺ also activates the cGAS-STING pathway, thereby reshaping the TME and enhancing chemotherapy for glioma. The multifunctional nanoplatform demonstrated a notable inhibition of tumor growth in comparison to the control groups. It is anticipated that this innovative approach may offer promising prospects for the management of malignant glioma in clinical management.