Overcoming intranasal delivery barriers with ultrastable polyzwitterionic siRNA nanocages for enhanced glioblastoma therapy

Abstract Intranasal administration presents a direct, non‐invasive pathway for delivering small interfering RNA (siRNA) to glioblastoma (GBM), but its efficiency is hampered by intranasal and intratumoral barriers. To overcome these barriers, here, we develop a multipotent nanocage system featuring a crosslinked yet reactive oxygen species (ROS)‐cleavable, zwitterionic poly (tertiary amine oxide) (PTAO) shell for efficient intranasal siRNA delivery. This design ensures ultrastable siRNA encapsulation under physiological conditions while enabling traceless siRNA release selectively in tumor cells with elevated ROS levels. Notably, the gene silencing efficacy of the nanocages remains unaffected after 1 month of room‐temperature storage in solution. By leveraging the zwitterionic property of PTAO, the nanocages exhibit prolonged intranasal residence and enhanced mucus penetration. Furthermore, they induce lipid raft‐dependent macropinocytosis and subsequent transcytosis that promotes brain accumulation via the trigeminal nerve pathway and enables deep tumor penetration. This endocytosis mechanism directs nanocages into the non‐degradative endoplasmic reticulum‐Golgi pathway for intracellular trafficking, bypassing lysosomal trapping. In an orthotopic GBM mouse model, intranasal administration of nanocages loading PLK1 siRNA significantly suppressed glioma growth and extended survival without obvious safety issues. Our study demonstrates the potential of the nanocage platform as an intranasal delivery vehicle, promising broad therapeutic applications in GBM and other neurological disorders.