Targeting The Epidermal Growth Factor Receptor In Non-small Cell Lung Cancer;the Effect Of Delivering Exogenous Plasmid Derived MiRNA/siRNA Via Liver As Biogenerator

Although small RNAs,including siRNA and miRNA,are emerging as promising therapeutic drugs,their delivery in vivo remains a significant challenge.In this study,we propose that living organs,particularly the liver,may serve as "biogenerators" to produce and deliver small RNAs.After injecting plasmids that express anti-EGFR siRNA into mice through the tail vein,majority of the plasmids are taken up by the liver,in which a considerable amount of anti-EGFR siRNA transcript is generated and packaged into microvesicles(MVs).The anti-EGFR siRNA transcript in MVs are released into the circulation,and further delivered to various tissues,including lungs,leading to EGFR downregulation.As an extension of this finding,we show that tail vein injection of anti-EGFR siRNA expressing plasmids significantly inhibits EGFR expression and tumor growth in an orthotopic tumor mouse model.In summary,our results identify the living organs such as liver as promising biogenerators to assemble and secrete exogenous plasmid-derived small RNAs.This novel approach may overcome the barriers of delivering small RNA in vivo.