Intercellular transfer of circ_0017636 via exosomal vehicles overcomes glioblastoma chemoresistance through ARRB1-mediated signaling restoration

Temozolomide (TMZ) resistance represents a primary cause of treatment failure and poor outcomes in glioblastoma (GBM). Exosome-mediated intercellular communication is increasingly recognized as a pivotal mechanism driving the dissemination of chemoresistance; however, the specific contribution of exosomal circular RNA cargos to this adaptive process remains elusive. This study systematically characterized the biological function of exosomal circ_0017636 in remodeling the TMZ-resistant microenvironment. We identified that circ_0017636 was significantly downregulated in TMZ-resistant tissues and correlated with poor prognosis. Mechanistically, circ_0017636 functions as a competing endogenous RNA that physically sponges miR-665 to de-repress Arrestin Beta 1 (ARRB1). Crucially, we isolated exosomes from sensitive cells and confirmed their identity via transmission electron microscopy (TEM) and marker analysis. Utilizing CD63-GFP fluorescent tracking, we visually demonstrated the efficient internalization of these vesicles by resistant recipient cells, confirming that circ_0017636 is physically packaged into these exosomes as a transferable cargo. Upon uptake, these circ_0017636-loaded exosomes effectively propagated chemosensitivity signals, significantly reducing the expression of the proliferation marker Ki-67 and the multidrug resistance protein P-glycoprotein (P-gp), thereby suppressing malignant phenotypes. Furthermore, vivo experiments confirmed that intratumoral delivery of circ_0017636-enriched exosomes significantly retarded xenograft tumor growth and overcame TMZ resistance. Collectively, this study elucidates a novel exosome-based communication axis, wherein circ_0017636 acts as a transferable tumor suppressor. Our findings suggest that leveraging exosomes as natural vehicles to deliver circ_0017636 represents a promising therapeutic strategy, while also indicating its potential as a diagnostic biomarker.