A nitric-oxide driven chemotactic nanomotor for enhanced immunotherapy of glioblastoma

Abstract The major challenges of immunotherapy for glioblastoma are that drugs cannot target tumor sites accurately and properly activate complex immune responses. Herein, we design and prepare a kind of chemotactic nanomotor loaded with brain endothelial cell targeting agent angiopep-2 and anti-tumor drug (Lonidamine modified with mitochondrial targeting agent triphenylphosphine, TLND). Reactive oxygen species and inducible nitric oxide synthase (ROS/iNOS), which are specifically highly expressed in glioblastoma microenvironment, are used as chemoattractants to induce the chemotactic behavior of the nanomotors. We propose a precise targeting strategy of brain endothelial cells-tumor cells-mitochondria. Results verified that the released NO and TLND can regulate the immune circulation through multiple steps to enhance the effect of immunotherapy, including triggering the immunogenic cell death of tumor, inducing dendritic cells to mature, promoting cytotoxic T cells infiltration, and regulating tumor microenvironment. Moreover, this treatment strategy can form an effective immune memory effect to prevent tumor metastasis and recurrence.