Zinc Sulfide-Based Hybrid Exosome-Coated Autophagy-Mediated H2S-sensitized PDT/chemotherapeutic Synergistic Nanoplatform for Targeted Treatment of Glioblastoma Stem-Like Cells in Orthotopic Mouse Glioblastoma Model

Abstract

Core-hybrid shell hydroxychloroquine (HCQ) loaded zinc sulfide (ZnS) nanoparticles were synthesized, characterized and evaluated for the treatment of glioblastoma 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 cells in orthotopic mouse glioblastoma model. ZnS acts as a photosensitizer for reactive oxygen species (ROS) production to inflict damage to organelles within glioblastoma cells. Hydroxychloroquine inhibits autophagic flux, which can subsequently lead to the accumulation of impaired organelles caused by the ROS. As a result, substantial selective damage to glioblastoma cells was realized owing to the hybrid exosomes guiding the anti-tumour 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.