Smart Magnetic Nanomaterials for the Remote Control of Microglia Activation as a Potential Therapy for Glioblastoma

Among central nervous system (CNS) diseases, glioblastoma (GBM) ranks first among the most aggressive primary tumors in adults and is associated with a high fatality rate globally. GBM is characterized by an infiltrative nature and high genetic heterogeneity, which make treatment very challenging. Today, the most common therapies are based on surgical resection, when possible, followed by radio-chemotherapy treatment; however, these procedures do not produce effective outcomes in the post-operative course due to the complex nature of the tumor, thus resulting into a high recurrence rate. Based on the previous considerations, further research is crucial to identify the mechanisms involved in the onset of this disease to achieve a more specific therapeutic response, as well as targeted therapies able to maximize the anti-cancer efficiency while minimizing potentially adverse effects on healthy tissues. Considering this objective, several studies were conducted on the cells involved in tumor development, among which microglia have gained much interest. Microglia, glial cells that support neurons, are responsible for ensuring the CNS well-being through various proinflammatory and anti-inflammatory actions modulated by the expression of different phenotypes (M1 and M2). Among the various innovative approaches aimed at modulating microglia activation, nanotechnology offers most promising strategies, for example by providing the immunomodulation of microglia acting remotely through an external stimulus. In this work, it is proposed an approach based on lipid magnetic nanovectors (LMNVs), consisting of a core composed by iron oxide nanoparticles (IONPs) embedded in a lipid matrix, to induce microglia activation towards a pro-inflammatory phenotype against GBM cells by application of an external alternating magnetic field (AMF). Following an in-depth characterization of these nano-systems, mainly in terms of size, morphology, surface charge, magnetic properties, chemical composition, and cytocompatibility, a thorough in vitro analysis was carried out to examine the effects on microglia. Finally, preliminary research was conducted on more complex in ovo models, constituted by spheroids of patient-derived GBM cells grafted into a quail embryo, capable of more accurately mimicking GBM in vivo micro-environment in terms of three-dimensionality and vascularization properties. The previously described GBM in ovo model was exploited to assess the GBM targeting efficiency of LMNVs coated with cell membranes derived from glioblastoma cells (CM-LMNVs). The study revealed that LMNVs are stable, biocompatible, and exhibit a strong ability to accumulate within cells. The application of an AMF effectively induced microglia to shift towards the proinflammatory M1 phenotype without the need for drugs, relying entirely on external stimulation. Concerning CM-LMNVs, the interaction between the nanoparticles and the tumor requires more investigation. Despite this, the obtained results offer promising prospects for the exploitation of these nanoparticles in mild hyperthermic therapies for microglial immunomodulation.