Abstract

Small interfere RNA (siRNA) has been considered as a highly promising therapeutic agent for human cancer treatment including glioblastoma (GBM), which is a fatal disease without effective therapy methods. However, the siRNA based GBM therapy is seriously hampered by a couple of challenges in siRNA brain delivery including poor stability, short blood circulation, low blood brain barrier (BBB) penetration and tumor accumulation as well as inefficient siRNA intracellular release. Herein, we successfully developed an Angiopep-2 (Ang) functionalized intracellular environment responsive siRNA nanocapsules (Ang-NCss(siRNA)) as a safe and efficient RNAi agent to boost the siRNA based GBM therapy. Our experimental results demonstrated that the developed Ang-NCss(siRNA) display long circulation in plasma, efficient BBB penetration capability, GBM accumulation and retention as well as responsive intracellular siRNA release due to the unique design of small size (25 nm) with polymeric shell for siRNA protection, Ang functionalization for BBB crossing and GBM targeting, and disulfide bond as a linker for intracellular environment responsive siRNA release. Such superior properties of Ang-NCss(siRNA) result in outstanding growth inhibition of orthotopic U87MG xenografts without causing adverse effect, achieving remarkably improved survival benefits. The developed siRNA nanocapsules provide a new strategy for RNAi therapy of GBM and beyond.