Engineering Glioma-Cell-Derived Exosomes as Trojan Horse for Precisely Targeted Chemotherapy of Glioblastoma

The management of glioblastoma multiforme (GBM) remains challenging due to its poor prognosis and extremely high postoperative recurrence rate. Although the Gliadel wafer locally delivers carmustine, its clinical application is limited by suboptimal therapeutic efficacy and poor conformability to irregular resection cavities. To overcome these limitations, we developed a novel drug delivery system based on thermosensitive injectable chitosan-β-glycerol phosphate hydrogel containing doxorubicin-loaded mesoporous silica nanoparticles encapsulated within tumor-derived exosomes (Exo-DMSNs@CS). In an orthotopic mouse GBM relapse model recapitulating clinical tumor resection, the liquid Exo-DMSNs@CS formulation was injected into the surgical cavity and subsequently gelated in situ, achieving seamless adhesion to the irregular resection margins of the cavity. The exosome-coated nanoparticles (Exo-DMSNs), released gradually from chitosan hydrogel, exhibited enhanced tumor-targeting capability via exosome-mediated tumor-homing performance, thereby substantially promoting drug internalization. Compared to non-exosomal controls (DMSNs@CS), Exo-DMSNs@CS markedly suppressed tumor recurrence and prolonged survival. Our findings demonstrate that this Trojan-horse-inspired delivery strategy—leveraging tumor-derived exosomes to encapsulate drug-loaded nanoparticles—enables a localized and precise tumor-targeted drug delivery system, representing a promising therapeutic paradigm for GBM treatment.