ABSTRACT Glioblastoma (GBM) remains a significant therapeutic challenge. While GBM‐derived extracellular vesicles (EVs) are known to remodel the normal blood‐brain barrier (BBB) into a blood‐tumour barrier (BTB), the underlying mechanism is largely not understood. Here, we reveal that nucleolin (NCL) is transferred via GBM‐derived EVs to the surface of brain endothelial cells, where it promotes BTB formation. Furthermore, the NCL‐specific aptamer AS1411 exploits this pathway, crossing the BTB through receptor‐mediated transcytosis and selectively entering GBM cells in an NCL‐dependent manner. Proteolysis‐targeting chimeras (PROTACs), heterobifunctional molecules that recruit E3 ligases to degrade target proteins, show therapeutic potential but are hindered by inefficient brain penetration in GBM. Capitalizing on the BTB‐penetrating capability of AS1411 and our prior finding that AS1411 can intracellularly recruit the E3 ligase MDM2 via employing NCL as a molecular bridge, we engineered AS1411‐based PROTACs against VEGFR2 and EGFR. These PROTACs induced NCL‐ and MDM2‐dependent ubiquitination and degradation of VEGFR2 or EGFR in GBM cells, demonstrating potent anti‐tumour activity. Collectively, our findings identify EV‐transferred NCL as a key mediator of BTB formation and a functional transcytosis receptor for AS1411, providing a promising strategy for developing BTB‐permeable, targeted therapy for GBM.
Chen et al. (Wed,) studied this question.