Although the T_m drops ∼6 °C/modification (note: T_m loss is ∼10 °C/mismatch) in the oxetane, [1-(1′,3′-O-anhydro-β-D-psicofuranosyl)thymine, T], modified antisense (AON)–RNA heteroduplexes, the relative rates of the complementary RNA cleavage by RNase H remain the same as or comparable to that of the native counterpart. The RNA cleavage in the native hybrid duplex was 68 ± 3% (T_m = 44 °C), whereas it was found to be 64 ± 10% for the single T modified AON–RNA duplex (T_m = 39 °C), 56 ± 9% for the double T modified AON–RNA duplex (T_m = 33 °C) and 60 ± 7% for the triple T modified AON–RNAs (T_m = 26 °C). The oxetane modifications in AON reduce the endonuclease cleavage (DNase 1) significantly. One modification gives ∼2-fold protection and three modifications give ∼4-fold protection compared to that of the native. Introductions of both interior oxetane modifications in conjunction with the 3′-DPPZ (dipyridophenazine) group give the resulting AON–RNA hybrid an RNase H cleavage rate at least the same as that of the native counterpart, which, additionally, gives full stability against both exo- and endonucleases. The conformational transmission of the constrained 3′-endo sugar of the oxetane nucleotide in the AON strand is found to be transmitted up to a stretch of five nucleotides in the heteroduplex as is evident by the RNase H resistance to the cleavage of the complementary RNA strand, thereby showing that this five-nucleotide region most probably takes up a local RNA–RNA type conformation. This is the first report of an antisense oligonucleotide construct which fulfils three important criteria simultaneously: (1) the modified AON promotes the complementary RNA cleavage by RNase H at an efficiency comparable to that of the native counterpart, (2) the modified AON has substantially more endonuclease stability than that of the native AON, and finally, (3) the DPPZ group at the 3′-end provides the expected exonuclease stability. This also shows that the T_m increase of the AON–RNA hybrid duplex is not mandatory for RNase H promoted destruction of the target RNA.