Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor in adults, characterized by high invasiveness, resistance to therapy, and a low median survival. Physiological barriers of the central nervous system (CNS), the blood-brain barrier (BBB) and the blood–cerebrospinal fluid (CSF) barrier, limit drug delivery, representing a challenge for treatment. To overcome these limitations, nanoparticles (NPs)-based delivery systems that can cross the BBB and release drugs in a controlled manner have been developed. However, this approach also presents challenges such as rapid clearance by the immune system and limited distribution within the tumor microenvironment (TME). Cell-mediated transport, exploiting the natural migration ability of immune cells, offers a promising strategy to overcome these obstacles.