Glioblastoma multiforme (GBM) is a grade IV glioma originating from astrocytic glial cells and one of the deadliest tumors of the central nervous system (CNS), with an expected survival below 15 months. Standard therapies combining surgical resection, radiotherapy, and chemotherapy with temozolomide are often ineffective, as GBM invasiveness hampers the complete tumor removal, promoting recurrence. Furthermore, the complexity and heterogeneity of the tumor microenvironment (TME) hinders drug efficacy, while the presence of the blood-brain barrier (BBB) prevents the passage into the nervous vascular compartment. Recently, new drug delivery systems (DDS) have been designed to facilitate the accumulation of small molecules in the tumor and improve targeted treatments.