Glioblastoma multiforme (GBM) is a formidable cancer to treat due to the lack of effective drugs that can also efficiently cross the blood-brain barrier (BBB). Herein, a novel strategy involving the synthesis of p28 peptide-conjugated, lexiscan (LEX)-loaded, bardoxolone methyl (BM) self-assembled nanoparticles, designated as p28-LBM NPs, is introduced. These NPs are designed to overcome the dual challenges of effectively killing GBM cells and efficiently penetrating the brain. The p28 peptide is chosen for targeted delivery to brain tumors, and LEX is employed to enhance drug penetration across the BBB. The successful penetration of brain tumors by the p28-LBM NPs after intravenous administration is demonstrated, with BM delivered as part of the NPs significantly inhibiting GBM tumor growth and extending the survival of mice with tumors. In conclusion, the p28-LBM NPs present a promising approach for GBM treatment, with potential for effective and safe clinical applications in the future.