Glioblastoma multiforme (GBM) is the most common and aggressive malignant brain tumor, with a poor prognosis. Temozolomide (TMZ) represents the standard chemotherapy for GBM but has limited efficacy due to poor targeting and a hypoxic tumor microenvironment (TME). To address these challenges, we developed a dual-gas-releasing, cancer-cell-membrane-camouflaged nanoparticle to deliver TMZ. This nanoceria, camouflaged with a cancer cell membrane (CCM-CeO2), targets explicitly GBM cells and accumulates in lysosomes, triggering the rapid release of TMZ. Additionally, CCM-CeO2 could release oxygen (O2) and nitric oxide (NO) in response to the TME. Synthesized using d-arginine, catalytic nanoceria could decompose excessive hydrogen peroxide (H2O2) in the TME to produce O2, while d-arginine could nonenzymatically react with H2O2 to generate NO. CCM-CeO2 could penetrate GBM spheroids to a depth of 148.3 ± 31 μm, with the O2 and NO produced, reducing HIF-1α protein expression. When loaded with TMZ, CCM-CeO2 could increase the intracellular ROS produced by TMZ, leading to lysosome membrane permeabilization and notably augmented apoptosis and necrosis in GBM cells. An in vitro antitumor assay using spheroids showed that CCM-CeO2 reduced the IC50 value of TMZ from 174.5 to 42.6 μg/mL, likely due to the catalase-like activity of nanoceria. These results suggest that alleviating hypoxia and increasing ROS produced by chemotherapeutics could be an effective therapeutic strategy for treating GBM.
Keywords: apoptosis and necrosis; cancer cell membrane; lysosome; nanoceria; nitric oxide; oxygen; reactive oxygen species; temozolomide.