Antisense oligodeoxynucleotides (AS ODN) have been employed as gene-silencing agents in the laboratory and, in the clinic. The in vivo use of these molecules has been facilitated by chemical modifications to the DNA backbone which augment their nuclease stability. Attempts to further improve the efficacy of AS ODN have largely focused on 2' alterations of the ribose sugar that make the molecules more RNA like in structure. This increases the T(m) of formed DNA/RNA hybrids but simultaneously prevents binding of RNaseH which is important for ODN effectiveness. Herein, we demonstrate the use of AS ODN containing nucleosides with a novel oxetane (OXE) modification [oxetane, 1-(1', 3'-O-anhydro-beta-D-psicofuranosyl nucleosides)] which augments Tm, enhances nuclease stability, and is permissive of RNaseH activation. We also illustrate herein the value of rational targeting of OXE modified, and by analogy, AS ODN of any chemical modification.