Nano-catalytic carbon dot disrupts hypoxia-driven cascade reaction and ameliorates temozolomide-mediated glioblastoma suppression

Glioblastoma (GBM), the most aggressive WHO grade 4 brain tumor, has a median survival of ~15 months and a five-year survival rate of only 7%. The current surgical and chemotherapeutic approaches remain insufficient for its treatment. A major obstacle in its treatment is the presence of hostile tumor microenvironment (TME), marked by severe hypoxia, elevated H2O2 and acidic pH, which promotes resistance to the standard drug, Temozolomide (TMZ). Hypoxia, orchestrated by HIF-1α, stabilizes TMZ in its inactive form, reducing its efficacy. To address this, we developed plant-based carbon dots (ASA@p-CD, ~8 nm) with catalase, peroxidase, glycosidase, and phosphatase-like multienzyme activities that enhance active TMZ conversion by ~1.27 fold. In U-87 MG cells, ASA@p-CD + TMZ treatment increased cytotoxicity by ~2.71 fold while ASA@p-CD alleviated hypoxia, reducing HIF-1α by ~1.5 fold and ROS by ~2.0 fold. Overall, this suppressed hypoxia signalling, impaired DNA repair and enhanced apoptosis, established ASA@p-CD as a TME-responsive, bifunctional nano-catalytic agent which may pave the path for future cancer therapeutics.