The present invention provides a chemically modified siRNA molecules and methodsof using such siRNA molecules to silence target gene expression. Advantageously,the modified siRNA of the present invention is less immunostimulatory than itscorresponding unmodified siRNA sequence and retains RNAi activity againstthe target sequence. The present invention also provides nucleic acid-lipidparticles comprising a modified siRNA, a cationic lipid, and a non-cationiclipid, which can further comprise a conjugated lipid that inhibits aggregationof particles. The present invention further provides methods of silencing geneexpression by administering a modified siRNA to a mammalian subject. Methodsfor identifying and/or modifying an siRNA having immunostimulatory propertiesare also provided.
