All-stage targeted nanodiscs for glioma treatment by inducing cuproptosis and apoptosis of cancer cells and cancer stem cells

There remain several intractable challenges for chemotherapy in glioma treatment, including the blood-brain barrier (BBB), blood-brain tumor barrier (BBTB), and tumor heterogeneity caused by cancer stem cells (CSCs), which are resistant to conventional chemotherapy. Here, we established a nano strategy to kill glioma cells and CSCs, combining carfilzomib and bis(diethyldithiocarbamate)copper. The synergistic drug combination disturbed cell protein metabolism at different stages and induced apoptosis and cuproptosis. The Y-shaped targeting ligand pHA-VAP-modified nanodiscs were designed to help the chemotherapeutic agents cross the BBB/BBTB and finally accumulate in tumor site. This all-stage targeting and all-stage treatment nanomedicine significantly prolonged the survival in glioma-bearing mice and might inspire the rational design of advanced drug delivery platforms. Challenges for chemotherapy in glioma include the blood-brain barrier (BBB), blood-brain tumor barrier (BBTB), and tumor heterogeneity caused by cancer stem cells (CSCs), which are resistant to conventional chemotherapy. A novel strategy for glioma-targeted treatment was established, combining carfilzomib (CFZ) and bis(diethyldithiocarbamate)copper (CuET) in Y-shaped peptide pHA-VAP (pV)-modified nanodiscs (pV-ND(CFZ/CuET)), which exhibited superior BBB/BBTB penetrating abilities. The strong synergistic drug combination eliminated both glioma cells and CSCs by inducing apoptosis and cuproptosis through disrupting the ubiquitin-proteasome system, and meanwhile reduced CFZ resistance of CSCs. This all-stage targeting and treatment strategy significantly prolonged the survival in glioma-bearing mice and might inspire the rational design of advanced drug delivery platforms.