Treating brain tumors presents enormous challenges, and there are still poor prognoses in both adults and children. Application of novel targets and potential drugs is hindered by the function of the blood-brain barrier, which significantly restricts therapeutic access to the tumor. Mesenchymal stem cells (MSCs) can cross biological barriers, migrate to sites of injuries to exert many healing effects, and be engineered to incorporate different types of cargo, making them an ideal vehicle to transport anti-tumor agents to the central nervous system. Extracellular vesicles (EVs) produced by MSCs (MSC-EVs) have valuable innate properties from parent cells, and are being exploited as cell-free treatments for many neurological diseases. Compared to using MSCs, targeted delivery via MSC-EVs has a better pharmacokinetic profile, yet avoids many critical issues of cell-based systems. As the field of MSC therapeutic applications is quickly expanding, this article aims to give an overall picture for one direction of EV-based targeting of brain tumors, with updates on available techniques, outcomes of experimental models, and critical challenges of this concept.

Metastasis of medulloblastomas (MBs) is difficult to treat and remains the primary cause of death in children with this brain tumor. Current treatment focuses on radiotherapy to limit metastatic recurrence and maintain survival, but this may cause long-term neurocognitive deficits. This challenge emphasizes the need for novel targeted therapies to combat metastatic MB. In this study, we report an RNA therapy model using targeted extracellular vesicles (EVs) to deliver therapeutic small-interfering (si)RNAs to MB. First, MB-targeted EVs (MB-tEVs) were generated via genetic modification of EV-producing cells to express E1-3, an MB-specific peptide. Next, isolated MB-tEVs were loaded with siRNAs that targeted LOXL1-AS1, a pro-metastatic long non-coding RNA in sonic-hedgehog MB (SHH-MB). Expression of the E1-3 peptide increased MB-tEV internalization into MB cells, where the delivered siRNAs effectively silenced LOXL1-AS1 and suppressed LOXL1-AS1-mediated metastatic traits of SHH-MB cells in vitro. Locoregional application of microbubble-enhanced focused ultrasound (FUS) improved the accumulation of systemically injected EVs in the mouse brain. Mice treated with siRNA-loaded MB-tEVs had decreased LOXL1-AS1 expression, reduced metastases, and improved survival in an SHH-MB orthotopic model. Our study provides the first and very promising evidence for the combined use of tumor-targeted EVs and microbubble-enhanced FUS to deliver therapeutic siRNAs to suppress metastatic MB, potentially supporting conventional treatments and improving clinical outcomes of this malignant pediatric tumor.