Glioblastoma (GBM) is the most aggressive primary brain tumor. With a mean survival of 15 months, it is urgent to investigate new molecules involved in cancer initiation and progression that can be used for targeted therapies. Several forkhead box (FOX) transcription factors have been identified in many mechanisms that promote therapy resistance and GBM progression. FOX factors appear to be involved in metabolism, increasing the interest in the field of brain tumors. This project aims to develop a novel therapeutic strategy by targeting the FOXO3a–FOXM1 axis using siRNA-loaded exosomeliposome hybrids (Exo-LIP). By combining this gene-silencing approach with the standard chemotherapeutic agent Temozolomide (TMZ), we seek to overcome therapy resistance and improve treatment efficacy. The project will involve the formulation and characterization of siRNA-loaded Exo-LIP, followed by the evaluation of safety and penetration of the nasal mucosa in nasal cell lines, assessment of its safety in brain cell lines, and testing of its therapeutic effect in 3D glioblastoma spheroid models.