Aptamer-functionalized exosomes combined with doxorubicin suppress GBM progression and enhance chemoradiosensitivity...

Glioblastoma (GBM) is the highly lethal intracranial tumor characterized by low survival rates and high recurrence, partly attributable to the challenges posed by the blood-brain barrier (BBB). To enhance therapeutic efficacy, the Exo-U2-Dox complex was engineered by functionalizing mesenchymal stem cell (MSC)-derived exosomes with the GBM-targeting aptamer U2 and integrating them with doxorubicin (DOX). This complex is designed to augment the sensitivity of GBM to chemo-radiotherapy. Here, it is found that Exo-U2 effectively accumulates in GBM-bearing mice, thereby inhibiting tumor progression. When administered in conjunction with DOX and radiation, Exo-U2-Dox increases DNA damage in GBM cells, and diminishes invasiveness. Mechanistically, Exo-U2 targets and inhibits the autophosphorylation of Epidermal growth factor receptor variant Ⅲ (EGFRvⅢ) in GBM cells, thereby activating the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome-mediated pyroptosis pathway, which leads to increased expression of Gasdermin D (GSDMD) and Cysteine-aspartic acid protease-1 (caspase-1), ultimately suppressing GBM cell proliferation, migration, and invasion. Furthermore, the combination of Exo-U2 with X-ray treatment inhibits the expression of p53-binding protein 1 (53BP1), reduces phosphorylation of the Ataxia-Telangiectasia Mutated/Checkpoint kinase 2 (ATM/Chk2) pathway, resulting in the accumulation of DNA damage. Collectively, these findings underscore the potential of aptamer-functionalized exosomes in conjunction with DOX as a promising strategy for GBM treatment. This approach not only broadens the therapeutic applications of DOX but also provides a novel direction for targeted GBM therapies.