Zinc Sulfide-Based Hybrid Exosome-Coated Nanoplatform for Targeted Treatment of Glioblastoma Stem-Like Cells in an Orthotopic Mouse Glioblastoma Model

Core-hybrid shell hydroxychloroquine (HCQ) loaded zinc sulfide (ZnS) nanoparticles were synthesized, characterized and evaluated for the elimination of glioblastoma stem-like cells in vitro and in vivo. These particles, denoted as HCQ@ZnS@exo@iRGD, consist of hollow ZnS nanoparticles loading with the autophagic inhibitor of hydroxychloroquine and covered by a hybrid shell containing exosomes (exo) and phosphatidylserine derived pH- and redox-responsive pegylated iRGD peptide, a gliomablastoma-homing and penetrating peptide. The hybrid exosomes enable HCQ@ZnS with good permeability across the blood-brain barrier and targeting ability to glioblastoma stem-like cells in orthotopic mouse glioblastoma model. ZnS acts as a photosensitizer for ROS production to inflict damage to organelles within glioblastoma cells. Hydroxychloroquine blocks autophagic flux, which can subsequently lead to the accumulation of impaired organelles caused by the ROS. As a result, substantial selective damage to glioblastoma stem-like cells was realized owing to the hybrid exosomes guiding the synergistic effects of hydroxychloroquine and ZnS under light irradiation. The results provide evidence for the utility of HCQ@ZnS@exo@iRGD as a therapeutic strategy for glioblastoma.