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Glioblastoma multiforme is a serious medical issue in the brain oncology field due to its aggressiveness and recurrence. Immunotherapy has emerged as a valid approach to counteract the growth and metastasization of glioblastoma multiforme. Among the different innovative approaches investigated, nanoparticles gain attention because of their versatility which is key in allowing precise targeting of brain tumors and increasing targeted drug delivery to the brain, thus minimizing adverse effects. This article reviews the progress made in this field over the past 2 years, focusing on nonspherical and biomimetic particles and on vectors for the delivery of nucleic acids. However, challenges still need to be addressed, considering the improvement of the particles passage across the blood–meningeal barrier and/or the blood–brain barrier, promoting the clinical translatability of these approaches.

Glioblastoma is the most common and aggressive brain tumor, associated with poor prognosis and survival, representing a challenging medical issue for neurooncologists. Dysregulation of histone-modifying enzymes (HDACs) is commonly identified in many tumors and has been linked to cancer proliferation, changes in metabolism, and drug resistance. These findings led to the development of HDAC inhibitors, which are limited by their narrow therapeutic index. In this work, we provide the proof of concept for a delivery system that can improve the in vivo half-life and increase the brain delivery of Givinostat, a pan-HDAC inhibitor. Here, 150-nm-sized liposomes composed of cholesterol and sphingomyelin with or without surface decoration with mApoE peptide, inhibited human glioblastoma cell growth in 2D and 3D models by inducing a time- and dose-dependent reduction in cell viability, reduction in the receptors involved in cholesterol metabolism (from −25% to −75% of protein levels), and reduction in HDAC activity (−25% within 30 min). In addition, liposome-Givinostat formulations showed a 2.5-fold increase in the drug half-life in the bloodstream and a 6-fold increase in the amount of drug entering the brain in healthy mice, without any signs of overt toxicity. These features make liposomes loaded with Givinostat valuable as potential candidates for glioblastoma therapy.

Simple Summary Communication between cells helps tumors acquire resistance to chemotherapy and makes the struggle against cancer more challenging. Tunneling nanotubes (TNTs) are long channels able to connect both nearby and distant cells, contributing to a more malignant phenotype. This finding might be useful in designing novel strategies of drug delivery exploiting these systems of connection. This would be particularly important to reach tumor niches, where glioblastoma stem cells proliferate and provoke immune escape, thereby increasing metastatic potential and tumor recurrence a few months after surgical resection of the primary mass. Along with the direct inhibition of TNT formation, TNT analysis, and targeting strategies might be useful in providing innovative tools for the treatment of this tumor. Abstract Glioblastoma (GBM) is a particularly challenging brain tumor characterized by a heterogeneous, complex, and multicellular microenvironment, which represents a strategic network for treatment escape. Furthermore, the presence of GBM stem cells (GSCs) seems to contribute to GBM recurrence after surgery, and chemo- and/or radiotherapy. In this context, intercellular communication modalities play key roles in driving GBM therapy resistance. The presence of tunneling nanotubes (TNTs), long membranous open-ended channels connecting distant cells, has been observed in several types of cancer, where they emerge to steer a more malignant phenotype. Here, we discuss the current knowledge about the formation of TNTs between different cellular types in the GBM microenvironment and their potential role in tumor progression and recurrence. Particularly, we highlight two prospective strategies targeting TNTs as possible therapeutics: (i) the inhibition of TNT formation and (ii) a boost in drug delivery between cells through these channels. The latter may require future studies to design drug delivery systems that are exchangeable through TNTs, thus allowing for access to distant tumor niches that are involved in tumor immune escape, maintenance of GSC plasticity, and increases in metastatic potential.