Deciphering nanoparticle trafficking into glioblastomas uncovers an augmented antitumor effect of metronomic chemotherapy.

Nanoparticles have been explored in glioblastomas as they can traverse the blood-brain barrier and target glioblastoma selectively. However, direct observation of nanoparticle trafficking into glioblastoma cells and their underlying intracellular fate after systemic administration remains uncharacterized. Here, based on transmission electron microscopy experiments of an intracranial glioblastoma model, we show that ligand-modified nanoparticles can traverse the blood-brain barrier, endocytose into the lysosomes of glioblastoma cells, and undergo endo-lysosomal escape upon photochemical ionization. Moreover, an optimal dose of metronomic chemotherapy using dual drug-loaded nanocarriers can induce an augmented antitumor effect directly on tumors, which was not recognized in previous studies. Metronomic chemotherapy enhances antitumor effects 3.5-fold compared with the standard chemotherapy regimen using the same accumulative dose in vivo. This study provides a conceptual framework that can be used to develop metronomic nanoparticle regimens as a safe and viable therapeutic strategy for treating glioblastomas and other advanced-stage solid tumors. This article is protected by copyright. All rights reserved.