Malignant glioma is one of the most common and severe brain diseases, which is extremely hard to treat due to the presence of the blood-brain barrier (BBB). Ultrasound (US) triggered sonodynamic therapy (SDT) is rapidly emerging as a noninvasive cancer treatment which benefits from the deep penetration of ultrasound waves. It has been reported that US can reversibly open the BBB for the enhancement of drug delivery. Therefore, a few researchers have paid attention to sonodynamic therapy for the in situ treatment of gliomas. Herein, we report the augmentation of SDT efficacy with the use of a combination of ultrasound-targeted microbubble destruction (UTMD) and iRGD modified DVDMS liposome (iRGD-Lipo-DVDMS), in which the sonoactivated sensitizer DVDMS (also called sinoporphyrin sodium) is loaded into the targeting liposomes and the sonodynamic effect is shown to boost the reactive oxygen species formation in response to focused US exposure. By using a strategy where the treatment was repeated twice with a five-day interval in between, where UTMD was first applied followed by iRGD-DVDMS injection and then focused US exposure, the orthotopically implanted C6 gliomas were greatly suppressed. Additionally, the median survival time increased to 40 days compared to 15 days in the control, 19 days in free DVDMS-SDT, and 24 days in general Lipo-DVDMS-SDT. Such targeted iRGD-Lipo-DVDMS mediated SDT also alleviated the body weight loss of tumor bearing mice because of the injury caused by orthotopic implantation, showing outstanding anti-glioma efficacy. After BBB opening with UTMD, the iRGD modified liposomes showed enhanced tumor targeting ability compared to the ones without iRGD modification, both in vivo and in vitro. The iRGD-Lipo-DVDMS exhibited significantly improved drug accumulation in monolayer cells, 3D tumor spheroids and transplanted C6 tumors, thus causing significant glioma cell apoptosis. Moreover, the developed targeting nanosonosensitizer (referred to as iRGD-Lipo-DVDMS) showed good in vivo biocompatibility and was promising in fluorescence image guided sonodynamic cancer therapy. Taken together, the established platform has considerable potential to enable the targeted delivery of sonodynamic treatment and would be an alternative strategy for glioma treatment.