Ruthenium-Based Nanoplatform for Glioblastoma Multiforme Therapy: Synergistic Photothermal/Photodynamic Effects Combined with Ferroptosis and Endoplasmic Reticulum Stress

Glioblastoma multiforme (GBM) is difficult to surgically remove, leading to a high recurrence risk. Phototherapy targets residual cells postsurgery; however, the photosensitizers with low molar absorption coefficients and susceptibility to photodegradation attenuated the phototherapeutic efficacy. The treatment effectiveness for GBM has been limited owing to tumor heterogeneity and drug resistance; it is urgently needed to develop an effective chemotherapy strategy to improve the median survival of GBM patients. Herein, a multifunctional phototherapy nanoplatform (Fe3O4@PDA@Ru) has been developed, where iron oxide nanoparticles (Fe3O4) serve as the core and polydopamine (PDA) and methoxy polyethylene glycol amine (mPEG-NH2) as the shell, loaded with a Ru-based photosensitizer ([Ru(bpy)2(PYIP)]Cl2). Fe3O4@PDA@Ru could generate singlet oxygen and a stable photothermal effect under irradiation. Fe3O4@PDA@Ru underwent internalization via clathrin-dependent and caveolae-mediated endocytic pathways, with subsequent multiorganelle localization in the cytoplasm. Fe3O4@PDA@Ru synergistically inhibited tumor growth and activated ferroptosis and endoplasmic reticulum (ER) stress by inactivation of glutathione peroxidase 4 (GPX4), consumption of glutathione (GSH), accumulation of lipid peroxide, and upregulation of activating transcription factor 6 (ATF6). These findings offered a promising strategy to enhance PTT and PDT by promoting ferroptosis and ER stress in GBM therapy.