Enhanced nose-to-brain delivery of siRNA using hyaluronan-enveloped nanomicelles for glioma therapy

Gliomas are the most malignant brain tumors, and their treatment is very challenging because of the presence of the blood-brain barrier (BBB). Intranasal administration has been considered a noninvasive strategy for glioma therapy in recent years, but our explorations of the intranasal delivery of siRNA-based therapies are still clearly inadequate. In this study, the cell-penetrating peptide DP7-C was enveloped with hyaluronic acid (HA) to develop the multifunctional core-shell structure nanomicelle HA/DP7-C. In vitro studies of HA/DP7-C revealed low cytotoxicity and a higher cell uptake efficiency, which was associated with the interaction between HA and CD44. In vivo experiments indicated that HA/DP7-C delivered the siRNA to the central nervous system through the trigeminal nerve pathway within hours after intranasal administration and that the interaction between HA and CD44 also increased its accumulation at the tumor site. Successful intracellular delivery of an antiglioma siRNA inhibited tumor growth and ultimately prolonged the survival time and decreased the tumor volume in GL261 tumor-bearing mice. In addition, toxicity tests on rats showed no adverse effects on the nasal mucosa and trigeminal nerves. In conclusion, HA/DP7-C is a potential intranasal delivery system for siRNAs in glioma therapy.