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 Ш (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. • The Exo-U2 complex demonstrates efficient blood-brain barrier penetration capabilities, enabling targeted accumulation at tumor sites. • The Exo-U2 complex significantly suppresses proliferation, migration, and invasion of gliblastoma in both in vitro and in vivo models. • The Exo-U2 complex triggers pyroptosis in U87EGFRvIII gliblastoma cells via the NLRP3-caspase-1-GSDMD signaling axis. • The Exo-U2-Dox complex notably enhances chemo-radiosensitivity, indicating its potential utility as a novel radiosensitizer.
Wang et al. (Sun,) studied this question.