Ultrasound-activated Piezoelectric Nanoparticles Trigger Microglia Activity against Glioblastoma Cells.

Glioblastoma multiforme (GBM) is the most aggressive brain cancer, characterized by a rapid and drug-resistant progression. GBM "builds" around its primary core a genetically heterogeneous tumor-microenvironment (TME), recruiting surrounding healthy brain cells by releasing various intercellular signals. Glioma-associated microglia (GAM) represent the largest population of collaborating cells, which, in the TME, usually exhibit the anti-inflammatory M2 phenotype, thus promoting an immunosuppressing environment that helps tumor growth. Conversely, "classically activated" M1 microglia could provide pro-inflammatory and anti-tumorigenic activity, expected to exert a beneficial effect in defeating glioblastoma. In this work, we proposed an immunotherapy approach based on pro-inflammatory modulation of the GAM phenotype, through a controlled and localized electrical stimulation. The developed strategy relies on the wireless ultrasonic excitation of polymeric piezoelectric nanoparticles coated with GBM cell membrane extracts, to exploit homotypic targeting in anti-glioma applications. Such camouflaged nanotransducers locally generate electrical cues on GAM membranes, activating their M1 phenotype and ultimately triggering a promising anti-cancer activity. Collected findings open new perspectives in the modulation of immune cell activities through "smart" nanomaterials and, more specifically, provide an innovative auspicious tool in glioma immunotherapy. This article is protected by copyright. All rights reserved.