Nanosized carriers based on amphiphilic poly(-vinylpyrrolidone) (Amph-PVP) are a versatile delivery system for various therapeutic agents such as anti-inflammatory drugs and plasmid DNA, as well as targeted antitumor drugs and proteins. Earlier, we developed Amph-PVP-based nanoparticles decorated by a modified DR5-specific TRAIL variant DR5-B (PVP-DR5-B) or containing the proteasomal inhibitor bortezomib (PVP-BTZ). Both DR5-B and BTZ have antitumor properties and, when combined, act synergistically on tumor cells. In the present study, Amph-PVP nanoparticles were loaded with BTZ and subsequently decorated with the TRAIL variant DR5-B, producing a dual polymeric bionanocomposite system PVP-BTZ-DR5-B. Using 2D and 3D cultures of human glioblastoma cell lines U87MG and T98G, it was demonstrated that PVP-BTZ-DR5-B nanoparticles were internalized and accumulated in cells more efficiently, demonstrating significantly enhanced cytotoxicity compared to free DR5-B or PVP-BTZ nanoparticles loaded with bortezomib alone. PVP-BTZ-DR5-B nanoparticles also penetrated the blood-brain barrier more efficiently than DR5-B in an model. Finally, the enhanced antitumor effect of PVP-BTZ-DR5-B was demonstrated in a xenograft model of U87MG glioblastoma cells in zebrafish embryos . Thereby, coloading of BTZ and DR5-B into the Amph-PVP nanoparticles is a promising approach to enhance the antitumor efficacy of free drugs and overcome glioblastoma resistance.