An efficient method for the preparation of siRNAs modified with ribo-like North bicyclo[3.1.0]hexane pseudosugars is described. The combined use of 2鈥?O-(2-cyanoethoxymethyl) (CEM) and 2鈥?O-TBDMS protection was successfully employed for RNA synthesis with the added advantage that both groups were efficiently removed in a single step. The resulting North ribo-methanocarba-modified siRNAs are compatible with the intracellular RNAi machinery and can mediate specific degradation of target mRNA.