Catalytic nanoreactors promote GLUT1-mediated BBB permeation by generating nitric oxide for potentiating glioblastoma ferroptosis

Glioblastoma, the most common malignant brain tumor with a poor prognosis, still needs to develop effective therapeutic strategies to prolong the patient's survival. Inducing GBM tumor cell ferroptosis could be the specific assay to improve GBM therapeutic efficiency. In comparison, ferroptosis in GBM cells is limited by the low intracellular ferrous ion concentration and oxidation resistance. Herein, an MNP-based ferroptosis catalytic nanoreactor loading cisplatin (CMNP-Cis-Arg) was designed to evaluate their targeted delivery and therapeutic efficiency in GBM treatment. The ferroptosis catalytic nanoreactors achieved an effective GBM targeted transportation via chitosan oligosaccharide driven GLUT1-mediated BBB permeabilization and arginine-based tumor chemotactic. CMNP-Cis-Arg improves synergistically lipid oxidation in GBM cells by inducing ROS generation and depleting intracellular GSH. The MNPs elevate ROS levels in tumor cells by enhancing Fe2+-based Fenton reaction and the encapsulated cisplatin as a chemotherapy agent depleting GSH via inducing the DNA strand broken. Moreover, the CMNP-Cis-Arg further induces NO biosynthesis and generates ONOO– with high oxidability to increase lipid oxidation. The anti-GBM ability of the CMNP-Cis-Arg was evaluated both in vitro and in vivo, significantly inducing the GBM tumor cells' apoptosis and reducing the tumor burden in an orthotopic mouse model. The investigation provided a novel ferroptosis catalytic nanoreactor and confirmed their anti-GBM efficiency in boosting tumor intracellular ferroptosis, suggesting a potential therapeutic strategy worth further investigating preclinically.