Piezodynamic Therapy: Unleashing Mechanical Energy and Featuristic Next Generation Therapeutic Paradigms for Glioblastoma

Glioblastoma (GBM), the most lethal primary brain tumor in adults, is characterized by extensive infiltration, marked heterogeneity, and resistance to conventional therapies. The blood-brain barrier (BBB) impedes effective drug delivery; therefore, recent advancements in energy-based therapies have introduced innovative approaches to overcome these challenges. These include focused ultrasound, tumor-treating fields, magnetomechanical actuation, and triboelectric stimulation to transiently disrupt the BBB and facilitate targeted treatment. Piezodynamic therapy has emerged as a key strategy, using piezoelectric nanomaterials to convert mechanical stimuli into reactive oxygen species (ROS) and immunogenic signals, inducing localized oxidative stress and immune activation. This approach is complemented by nanogas-based technologies, which enhance spatiotemporal control over ROS generation through ultrasound-driven piezocatalysis. Novel 3D-bioprinted GBM models provide patient-specific platforms for optimizing these therapies and investigating piezodynamic effects in realistic tumor environments. Concurrently, implantable smart devices enable real-time modulation of mechanical stimuli, improving treatment precision. Tumor vaccines also play a complementary role by amplifying systemic anti-GBM immune responses. Challenges such as nanoparticle biocompatibility, precise regulation of physical stimuli, and clinical translation persist. This review evaluates the existing energy-based multimodal treatments and integration of piezodynamic therapy with nanogas technologies, 3D bioprinting, and immune-stimulating vaccines, highlighting their potential as a featuristic strategy to overcome GBM's therapeutic resistance.