Ultrasound-Activated Biodegradable Piezoelectric Chitosan Nanoparticles for Glioblastoma Treatment

Piezoelectric nanomaterials are highly promising for remote cell stimulation due to their ability to convert mechanical energy, such as ultrasound (US), into electrical cues that modulate cellular behavior. In the context of cancer treatment, piezoelectric stimulation has recently shown antiproliferative, chemosensitizing, antiangiogenic, and immunomodulatory effects. Despite growing interest in organic alternatives, no biodegradable or bioabsorbable nanoparticles with clinically approved components have yet been developed with piezoelectric properties for cell stimulation, limiting the translational potential of this approach. Here, chitosan nanoparticles (ChNPs) have been engineered to exhibit intrinsic piezoelectric properties, enabling US-mediated activation. Their structural, mechanical, and piezoelectric characteristics have been investigated using advanced physicochemical and electromechanical techniques. Biological evaluation of US-driven ChNPs-assisted piezostimulation has been tested on patient-derived glioblastoma cells. When stimulated with US, ChNPs demonstrate not only excellent antiproliferative activity, but also proapoptotic efficacy, even in the absence of any chemotherapeutic agent. This drug-free anticancer stimulation approach is attributed to reactive oxygen species generation triggered by the ChNP piezocatalytic properties. The antitumor activity is further validated in more complex ex ovo models. The combination of piezoelectric responsiveness, biodegradability, and preclinical feasibility highlights the potential of ChNPs as a safe, noninvasive therapeutic platform for next-generation cancer treatments.