Glioblastoma multiforme (GBM) is a devastating primary tumor of the central nervous system with a significantly poor prognosis. The primary challenge in treating GBM lies in the restrictive nature of the blood-brain barrier (BBB), impeding effective drug delivery to the brain. In this study, intranasal polymeric micelles encapsulating a quercetin-etoposide combination were developed to induce synergistic apoptotic effects and enhance direct drug delivery to the brain. However, the in vivo anticancer efficacy of the unmodified micelle formulation via intranasal administration remains limited. Therefore, this aims to investigate the enhancement of the formulation by conjugating the micelles with a novel and highly potent cell-penetrating peptide (CPP), RMMR1, identified using the intra-dermal delivery technology platform developed by REMEDI Co., Ltd. This modification seeks to enhance the brain-targeting capability of the micelles. The CPP-modified micelles encapsulating the quercetin-etoposide combination (CM(QE)) demonstrated superior in vivo brain-delivery efficiency and enhanced cellular uptake after intranasal administration. Furthermore, animal studies showed significant tumor reduction and increased survival rates, with no significant changes in body weight observed. These findings suggest that intranasal administration of CM(QE) holds promise as a significant advancement in chemotherapy for GBM.