Core-Shell Lipoplexes Inducing Active Macropinocytosis Promote Intranasal Delivery of c-Myc siRNA for Treatment of Glioblastoma

Glioblastoma is the most common and aggressive primary brain tumor, whose malignancy is closely correlated with elevated proto-oncogene c-myc. Intranasal administration emerges as a potential approach to deliver gene into the brain and interfere c-Myc expression. However, powerful permeability in nasal mucosa, selective delivery to glioma and avoidance of premature release during remote transport are imperative to ensure the therapeutic effectiveness. To address the above concerns, herein we constructed a lipoplex based on pre-compression of c-Myc-targeting siRNA (sic-Myc) by octaarginine and subsequent encapsulation by liposome modified with a selected peptide derived from penetratin, named 89WP. It was found that the lipoplex exhibited a stable core-shell structure and could be preferentially internalized along with cell debris by glioma cells via active macropinocytosis. Through this cellular uptake pathway, the lipoplex avoided being entrapped by lysosome and released siRNA in cytoplasm within 4 h, inducing substantial downregulation of c-Myc mRNA and protein expression of glioma cells. Furthermore, due to significantly enhanced permeability in tumor spheroids and nasal mucosa, the lipoplex was competent to deliver more siRNA to orthotopic glioma after intranasal administration, and therefore prolonged the survival time of glioma-bearing mice by inducing apoptosis.