Lipoprotein-Biomimetic Nanostructure Enables Efficient Targeting Delivery Of SiRNA To Ras-Activated Glioblastoma Cells Via Macropinocytosis

Ras is hyperactivated in a high percentage of tumors whereas inhibition of this oncogenic pathway remains unsuccessful.Macropinocytosis plays a crucial role in the internalization of protein in Ras-activated cancer cells.By utilizing this unique endocytosis pathway,here we developed a biologically-inspired nanostructure that can induce the cancer cells to 'drink' for targeting therapy,in which apolipoprotein E3-reconstituted high density lipoprotein(rHDL)possessing blood-brain barrier(BBB)permeability was used to encapsulate a siRNA-loaded calcium phosphate(CaP)core,forming the final nanostructure named siRNA-loaded CaP-rHDL,to enable targeting delivery of siRNA to Ras-activated glioblastoma multiforme(GBM)cells.The resulted CaP-rHDL nanostructure showed macropinocytosis-dependent,specific and high intake in GBM cell line in vitro and in vivo.To evaluate the potential of CaP-rHDL as a nanoplatform for tumor-targeting siRNA delivery,siRNA to activate transcription factor-5(ATF5)which is known as an anti-apoptotic protein that is highly expressed in GBM but not normal brain tissues and essential for glioblastoma cells survival,was used as the model drug.Carrying ATF5 siRNA,the obtained nanomedicine exerted remarkable RNA-interfering(RNAi)efficiency,increased apoptosis,and significantly prolonged the survival of glioblastoma-bearing mice at a low siRNA dose without side effect.These findings prove the concept of precision nanomedicine design for targeting therapy of Ras-activated GBM.