Neutrophil Delivered Hollow Titania Covered Persistent Luminescent Nanosensitizer for Ultrosound Augmented Chemo/Immuno Glioblastoma Therapy

Abstract

Glioblastoma (GBM) is the most malignant brain tumor with unmet therapeutic demand. The blood-brain-barrier (BBB) and tumor heterogeneity limit the treatment effectiveness of various interventions. Here, an ultrasound augmented chemo/immuno therapy for GBM using a neutrophil-delivered nanosensitizer, is developed. The sensitizer is composed of a ZnGa₂ O₄ :Cr³⁺ (ZGO) core for persistent luminescence imaging and a hollow sono-sensitive TiO₂ shell to generate reactive oxygen species (ROS) for controlled drug release. Immune checkpoint inhibitor (Anti-PD-1 antibody) is trapped in the interior of the porous ZGO@TiO₂ with paclitaxel (PTX) loaded liposome encapsulation to form ZGO@TiO₂ @ALP. Delivered by neutrophils (NEs), ZGO@TiO₂ @ALP-NEs can penetrate through BBB for GBM accumulation. After intravenous injection, ultrasound irradiation at GBM sites initiates ROS generation from ZGO@TiO₂ @ALP, leading to liposome destruction for PTX and anti-PD-1 antibody release to kill tumors and induce local inflammation, which in-turn attractes more ZGO@TiO₂ @ALP-NEs to migrate into tumor sites for augmented and sustained therapy. The treatment enhances the survival rate of the GBM bearing mice from 0% to 40% and endows them with long-term immuno-surveillance for tumor recurrence, providing a new approach for precision therapy against GBM and other cancers.