An ultrasound-activated piezoelectric sonosensitizer enhances mitochondrial depolarization for effective treatment of orthotopic glioma

Despite the significant advancements in piezoelectric materials for sonodynamic therapy (SDT), the suppression of orthotopic glioma remains challenging, primarily due to the unclear mechanism and the restriction of bloodbrain barrier (BBB). Herein, we proposed that layered piezoelectric SrBi2Ta2O9 nanoparticles (SBTO NPs) could effectively depolarize the mitochondrial membrane potential (Delta Psi m) of glioma cells under ultrasound (US) exposure. The US-induced band bending in SBTO NPs enhanced redox ability, promoting an increase in reactive oxygen species (ROS) generation. The in vitro results proved that SBTO NPs selectively accumulated in mitochondria under US and induced apoptosis in a mitochondrial depolarization manner mediated by the generation of ROS and free charges. Furthermore, SBTO NPs could cross the BBB and then accumulate in gliomas through US/microbubbles (MBs) procedure and protein-mediated transport. The therapeutic effect of piezoelectric SBTO NPs mediated SDT was proved in the orthotopic glioma mouse model. As validated by the histopathological observation and the long-term evaluation, the good biocompatibility and biosafety of SBTO NPs make it possible for deep tumor therapy, and worthy for further preclinical study. Statement of significance: Employing piezoelectric sonosensitizers for sonodynamic therapy (SDT) has emerged as a promising strategy for cancer treatment; however, the unclear mechanism and blood-brain barrier (BBB) limit the effectiveness of SDT in glioma. Herein, we developed piezoelectric SrBi2Ta2O9 nanoparticles (SBTO NPs) with a built-in electric field for glioma treatment and explored the underlying therapeutic mechanism. Notably, SBTO NPs selectively accumulated in mitochondria under ultrasound (US) and induced apoptosis in a mitochondrial depolarization manner, which is mediated by the generation of reactive oxygen species (ROS) and free charges. In an orthotopic glioma mouse model, SBTO NPs were delivered into the glioma through US/microbubbles and transferrin-mediated transport pathways, inhibiting tumor growth. This work provides a new paradigm for the treatment of orthotopic glioma and other tumor types.