GelMA Hydrogel Loading circNEFM-Engineered Exosomes Inhibits Glioma Growth

Glioma is a highly malignant tumor of the central nervous system characterized by high morbidity, substantial drug resistance, and poor prognosis. Therapeutic challenges stem from the invasive growth of tumor cells, limited drug penetration through the blood-brain barrier (BBB), and widespread drug resistance induced by the tumor microenvironment. In recent years, biotherapeutic strategies based on the biological characteristics of circular RNAs (circRNAs) have emerged as promising avenues for glioma management. circNEFM functions as a competitive endogenous RNA (ceRNA) by sponging miR-1248 and miR-1236, thereby upregulating the expression of BCL6B and C1orf115. This molecular mechanism of circNEFM effectively inhibits tumor proliferation while sensitizing glioma cells to chemotherapy. However, conventional delivery systems have inherent limitations, including short systemic circulation time and inadequate local drug concentration. To overcome these challenges, in this study, we engineered a multifunctional GelMA hydrogel scaffold system that integrates three key advantages: the innate ability of exosomes to traverse the BBB while protecting their cargo from enzymatic degradation, aptamer-mediated precise tumor targeting, and the sustained release profile of GelMA hydrogels. This composite scaffold exhibited excellent biomechanical properties and enabled the controlled release of engineered exosomes loaded with circNEFM (exo-circNEFM). Notably, aptamer-functionalized exosomes exhibited enhanced specificity to glioma cells, leading to significant inhibition of cell proliferation through circNEFM-mediated pathways and effective reversal of chemoresistance. This innovative therapeutic platform represents a novel technological solution with considerable translational potential for glioma treatment.