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.

Discoidal nanoparticles showed highest blood-brain barrier permeability and transfer efficiency via tunneling nanotubes in glioblastoma cells, offering a promising strategy for nanoparticles delivery and intercellular distribution within tumors.

The cerebral synthesis of cholesterol is mainly handled by astrocytes, which are also responsible for apoproteins’ synthesis and lipoproteins’ assembly required for the cholesterol transport in the brain parenchyma. In Alzheimer disease (AD), these processes are impaired, likely because of the astrogliosis, a process characterized by morphological and functional changes in astrocytes. Several ATP-binding cassette transporters expressed by brain cells are involved in the formation of nascent discoidal lipoproteins, but the effect of beta-amyloid (Aβ) assemblies on this process is not fully understood. In this study, we investigated how of Aβ_1-42-induced astrogliosis affects the metabolism of cholesterol in vitro. We detected an impairment in the cholesterol efflux of reactive astrocytes attributable to reduced levels of ABCA1 transporters that could explain the decreased lipoproteins’ levels detected in AD patients. To approach this issue, we designed biomimetic HDLs and evaluated their performance as cholesterol acceptors. The results demonstrated the ability of apoA-I nanodiscs to cross the blood–brain barrier in vitro and to promote the cholesterol efflux from astrocytes, making them suitable as a potential supportive treatment for AD to compensate the depletion of cerebral HDLs.

Numerous studies are focused on nanoparticle penetration into the brain functionalizing them with ligands useful to cross the blood–brain barrier. However, cell targeting is also crucial, given that cerebral pathologies frequently affect specific brain cells or areas. Functionalize nanoparticles with the most appropriate targeting elements, tailor their physical parameters, and consider the brain's complex anatomy are essential aspects for precise therapy and diagnosis. In this review, we addressed the state of the art on targeted nanoparticles for drug delivery in diseased brain regions, outlining progress, limitations, and ongoing challenges. We also provide a summary and overview of general design principles that can be applied to nanotherapies, considering the areas and cell types affected by the most common brain disorders. We then emphasize lingering uncertainties that hinder the translational possibilities of nanotherapies for clinical use. Finally, we offer suggestions for continuing preclinical investigations to enhance the overall effectiveness of precision nanomedicine in addressing neurological conditions.This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Neurological Disease Therapeutic Approaches and Drug Discovery > Emerging Technologies

The influence of choline and geranic acid-based ionic liquids (CAGE ILs) on the anticancer activity of selected Pt(II) and Pt(IV) complexes was investigated. All complexes exhibited appreciable solubility in CAGE ILs, with Pt(II) complexes 2 and 4 undergoing immediate ligand substitution. In contrast, the hydrophobic derivative 3 demonstrated remarkable stability for up to 48 hours. ¹⁹F–¹H HOESY NMR analysis revealed that 3 localized within the hydrophobic regions of CAGE 1 : 2 (choline:geranate). When tested in U87-MG glioblastoma cells, CAGE ILs enhanced the anticancer activity of the Pt complexes. Notably, complex 3 exhibited a significant increase in cytotoxicity, nearly completely reducing cell viability when formulated with CAGE IL.

Cholesterol esterification is a fundamental step in cholesterol metabolism and transport, and in humans it is operated by three enzymes. Lecithin:cholesterol acyltransferase (LCAT) is responsible of cholesterol esterification in plasma and other biological fluids including cerebrospinal fluid (CSF), where it is mainly activated by apolipoprotein E. Esterification of cholesterol within cells is instead operated by sterol O-1 and O-2 acyltransferases (SOAT1 and SOAT2). SOAT1 is expressed in all cell types, while SOAT2 is expressed in hepatocytes and enterocytes, where it produces cholesteryl esters (CEs) to be assembled within VLDL and chylomicrons. LCAT and SOAT1/2 have different substrate specificity; LCAT has a preference for the unsaturated fatty acids, while the SOAT enzymes prefer the saturated and monounsaturated fatty acids. Here we show that CSF CEs have a different composition compared to plasma CEs and specifically are more enriched in saturated and monounsaturated fatty acids, typical substrates of the SOAT2 enzyme, and less frequently used by LCAT. Protein and RNA analysis in astrocytes, the main lipoprotein-producing cells in the central nervous system, excluded the presence of SOAT2, thus suggesting that CSF CEs are product of the LCAT enzyme. In line with this hypothesis, CSF phosphatidylcholine, the substate of LCAT, is enriched in saturated and monounsaturated fatty acids and depleted in polyunsaturated fatty acids. Moreover, we show that in AD patients, CSF CEs are enriched in saturated fatty acids, thus adding new insights into our recent observation that LCAT-mediated cholesterol esterification is hampered in AD. In conclusion, the present findings not only clarify the enzymatic origin of CSF CEs but also open avenues for developing enzyme-specific biomarkers and therapeutic strategies aimed at restoring lipid homeostasis in the brain.