Giammarino Pugliese

Polydopamine nanotubes (PDA-NTs) represent a recently developed and scarcely explored class of nanostructures with exceptional multifunctionality. Synthesized through a ZnO-templated Stöber-like process followed by template removal, PDA-NTs exhibit a combination of piezoelectric, photothermal, and antioxidant properties, a collection of features never observed together in a single organic nanoparticle. This work provides the demonstration of electromechanical conversion in polydopamine structures, with PDA-NTs showing a robust piezoelectric coefficient (d33 = 15.0 ± 0.7 pC/N), a property completely absent in spherical PDA nanoparticles. PDA-NTs are efficiently internalized by cells and display excellent biocompatibility; upon remote stimulation, they can modulate intracellular calcium levels via ultrasound-driven activation or near-infrared (NIR) photothermal heating. In addition, their strong antioxidant capacity mitigates oxidative stress, while controlled dopamine release (both passive and ultrasound-triggered) induces functional effects in human neural stem cells. This unique combination of mechanical and NIR responsiveness, antioxidant activity, and neuromodulatory drug release within a single organic nanostructure marks a significant breakthrough, allowing PDA-NTs to emerge as a unique class of “smart” multifunctional nanomaterials, enabling remote cellular control and offering exciting opportunities for regenerative medicine, neurostimulation, and advanced bioelectronics.

Microglia, the main immune cells in the central nervous system (CNS), maintain physiological homeostasis and react to pathological changes. Besides their neuroprotective function, they play a crucial role in brain tumor microenvironments such as glioblastoma (GBM), by composing up 40% of the tumor mass. Glioma-associated microglia exhibit a dynamic activation state characterized mainly by an immunosuppressive (M2-like) response, with a lesser contribution of pro-inflammatory (M1-like) response. Modulating microglial into M1-like phenotype offers antitumor response and a promising immunotherapy strategy against GBM. Nanoparticles can induce microglial polarization, also modulating pro-inflammatory responses for tumor suppression. Magnetically responsive nanoparticles are promising nanotransducers due to their remote-control capabilities via external magnetic fields, enabling precise therapeutic interventions. This study proposes a novel strategy that exploits lipid-based magnetic nanovectors (LMNVs) composed of a lipid matrix doped with iron oxide nanoparticles to induce M1-like microglial response through magneto-thermal conversion. Results demonstrated that LMNVs exhibit excellent biocompatibility and efficient internalization within human microglia (HMC3 cells). Upon alternating magnetic field (AMF) stimulation, LMNVs triggered a sustained increase in intracellular Ca²⁺ levels, leading to the polarization of microglia toward a pro-inflammatory M1-like phenotype. This activation was confirmed by the upregulation of key inflammatory markers (CD40, CD86) and cytokine release (IL-6, IL-8, and TNF-α), mirroring the effects of IFN-γ stimulation. These findings were further corroborated by comparative transcriptomic analysis. Notably, conditioned medium from LMNVs + AMF-stimulated microglia significantly impaired the viability and proliferation of both immortalized and patient-derived GBM cells, demonstrating a potent antitumor response. The tumor cell death was associated with immunogenic cell death (ICD), as indicated by the translocation of the damage-associated molecular patterns, in particular high mobility group box 1 (HMGB1) and calreticulin (CRT). Overall, these results highlight the potential of LMNVs as a remotely activatable nanoplatform capable of reprogramming microglia and to promote antitumor immunity in GBM.

Microglial cells play a critical role in glioblastoma multiforme (GBM) progression, which is considered a highly malignant brain cancer. The activation of microglia can either promote or inhibit GBM growth depending on the stage of the tumor development and on the microenvironment conditions. The current treatments for GBM have limited efficacy; therefore, there is an urgent need to develop novel and efficient strategies for drug delivery and targeting: in this context, a promising strategy consists of using nanoplatforms. This study investigates the microglial response and the therapeutic efficacy of dual-cell membrane-coated and doxorubicin-loaded hexagonal boron nitride nanoflakes tested on human microglia and GBM cells. Obtained results show promising therapeutic effects on glioma cells and an M2 microglia polarization, which refers to a specific phenotype or activation state that is associated with anti-inflammatory and tissue repair functions, highlighted through proteomic analysis.