Exosomes are small extracellular vehicles which could transport genetic materials and
proteins between cells. Although there are reports about exosomes crossing the blood-brain barrier (BBB), the underlying mechanisms still need further study. We found that exosomes from
primary brain tumors could upregulate the expression of
Lipocalin-2 (LCN2) in bEnd.3 brain microvascular endothelial cells (BMVECs). Furthermore, exosomes increased the membrane fluidity of bEnd.3 cells in an LCN2 dependent manner. Both
intraperitoneal injection and caudal vein injection of LCN2 increased the number of
nanocapsules crossing the BBB.
Evans Blue staining revealed that LCN2 does not interrupt the integrity of the BBB, as observed in the
traumatic brain injury model. Tandem mass tags quantitative proteomics and bioinformatics analysis revealed that LCN2 is upregulated by exosomes via the JAK-STAT3 pathway, but not delivered from exosomes. Knocking down LCN2 in bEnd.3 cells significantly abrogated the effect of exosomes on BMVEC membrane fluidity. Previously, we have reported that
2-methacryloyloxyethyl phosphorylcholine (MPC) and a
peptide crosslinker could encapsulate mAbs to achieve
nanocapsules. The
nanocapsules containing
choline analogs could effectively penetrate the BBB to deliver therapeutic
monoclonal antibodies (tAbs) to the
glioma. However, the delivered tAbs could be significantly reduced by blocking the release of exosomes from the
gliomas. Application of tAb
nanocapsules prior to treatment with
MK2206, an AKT pathway inhibitor that has been shown to inhibit the production of exosomes, resulted in a better combination. Insights from this study provide a mechanistic framework with regard to how
glioblastomas hijack BMVECs using exosomes. In addition, we provide a strategy for maximizing the effect of the
choline-containing
nanocapsules and
MK2206 combination. These results also demonstrate the therapeutic role of tAbs in
glioblastoma and
brain tumor metastasis, by shedding new light on strategies that can be used for BBB-penetrating
therapies.