Glioblastoma multiforme (GBM), also known as grade IV astrocytoma, represents the most aggressive primary brain tumor. The complex genetic heterogeneity, the acquired drug resistance, and the presence of the blood-brain barrier (BBB) limit the efficacy of the current therapies, with effectiveness demonstrated only in a small subset of patients. To overcome these issues, here we propose an anticancer approach based on ultrasound-responsive drug-loaded organic piezoelectric nanoparticles. This anticancer nanoplatform consists of nutlin-3a-loaded ApoE-functionalized P(VDF-TrFE) nanoparticles, that can be remotely activated with ultrasound-based mechanical stimulations to induce drug release and to locally deliver anticancer electric cues. The combination of chemotherapy treatment with chronic piezoelectric stimulation resulted in activation of cell apoptosis and anti-proliferation pathways, induction of cell necrosis, inhibition of cancer migration, and reduction of cell invasiveness in drug-resistant GBM cells. Obtained results pave the way for the use of innovative multifunctional nanomaterials in less invasive and more focused anticancer treatments, able to reduce drug resistance in GBM.

Accumulation of reactive oxygen species in cells leads to oxidative stress, with consequent damage for cellular components and activation of cell-death mechanisms. Oxidative stress is often associated with age-related conditions, as well as with several neurodegenerative diseases. For this reason, antioxidant molecules have attracted a lot of attention, especially those derived from natural sources—like polyphenols and tannins. The main issue related to the use of antioxidants is their inherent tendency to be oxidized, their quick enzymatic degradation in biological fluids, and their poor bioavailability. Nanomedicine, in this sense, has helped in finding new solutions to deliver and protect antioxidants; however, the concentration of the encapsulated molecule in conventional nanosystems could be very low and, therefore, less effective. We propose to exploit the properties of tannic acid, a known plant-derived antioxidant, to chelate iron ions, forming hydrophobic complexes that can be coated with a biocompatible and biodegradable phospholipid to improve stability in biological media. By combining nanoprecipitation and hot sonication procedures, we obtained three-dimensional networks composed of tannic acid–iron with a hydrodynamic diameter of ≈200 nm. These nanostructures show antioxidant properties and scavenging activity in cells after induction of an acute chemical pro-oxidant insult; moreover, they also demonstrated to counteract damage induced by oxidative stress both in vitro and on an in vivo model organism (planarians).