Glioblastoma (GBM) belongs to the deadliest primary malignancies with high mortality rate and poor prognosis. Over the past decades, less progress has been made to treat GBM, owing largely to the lack of effective chemotherapeutics and poor drug accumulation in the glioma tissue. In order to address this issue, we present an efficient biomimetic nanocomposite (Cu2−xSe-CB@MEM, CCM), consisting of Cu2−xSe nanoparticle core modified by cinobufotalin (CB), a toad venom extract, which is camouflaged with glioma cell Ln229 membrane. It is demonstrated that CB can decrease the protein activity of inosine monophosphate dehydrogenase 1 (IMPDH1), a key target correlated with prognosis, through intermolecular hydrogen bonding with amino acid residues ARG-105 and ASP-77. The glioma cell membrane-camouflage endows the CCM with blood-brain barrier penetration and homology tumor-targeted ability. The optimized cinobufotalin based chemotherapy combining with the near-infrared-II (NIR-II) irradiation shows outstanding inhibition effect to glioma cells, by blocking cell cycle and inducing apoptosis. In vivo mice bearing orthotopic Ln229 GBM treated with CCM+NIR-II (CCM+L) have significantly suppressed tumor growth and extended survival, without side effect. The glioma cell membrane camouflaged nanocomposite of Cu2−xSe and cinobufotalin with its significant anti-glioma property and well biosafety will provide novel alternatives for clinical treatment of GBM.