Oxygen/Nitric Oxide Dual-Releasing Nanozyme for Augmenting TMZ-Mediated Apoptosis and Necrosis

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.