Ferroptosis is an emerging form of programmed cell death, and its combination with sonodynamic
therapy (SDT) for anti-
tumor activity is gradually attracting attention. However, their application against
gliomas has not been studied. Herein, multifunctional
cancer homologous targeting biomimetic nanoparticles (PIOC@CM NPs) encapsulating both Fe3O4 and Ce6 were constructed as a nanosonosensitizer. Based on focused ultrasound (US) combined with circulating
microbubbles (MBs) to open the blood-brain barrier (BBB) in a safe and transient manner, the development of a therapeutic strategy to integrate the biomimetic nanosonosensitizer-mediated SDT and ferroptosis could achieve synergistic
therapeutic effects against
gliomas. We demonstrated that the
glioma C6 cell membrane (CM) on the surface of the NPs allowed the nanosonosensitizer to accumulate selectively in
tumors through homologous targeting in vitro. After efficient internalization in C6 cells, the PIOC@CM NPs could significantly increase the level of
reactive oxygen species (ROS) and deplete
glutathione (GSH) upon ultrasonic irradiation, resulting in the loss of
glutathione peroxidase-4 (GPX4) activity, which facilitated SDT and ferroptosis to kill
glioma C6 cells. Furthermore, the PIOC@CM NPs were intravenously injected after noninvasively opening the BBB via US-MBs, which enhanced the accumulation of the nanosonosensitizer in
tumor tissues. Crucially, an attractive phenomenon of the significant reduction in orthotopic
gliomas after the second US pulse-triggered SDT and ferroptosis was observed. Taken together, this study presents a novel combinatorial
glioma therapeutic strategy based on noninvasive BBB opening with a biomimetic sonotheranostic system-mediated SDT and ferroptosis.