Chemical modification of therapeutic oligodeoxyribonucleotides (ODNs) is necessary to avoid not only degradation by endo- and exo-nucleases but also recognition by sensors such as an innate immune system. We have been developing modified nucleosides having an aminoalky linker at the pyrimidine nucleobase or sugar moiety. ODNs containing 5-N-(6-aminohexyl)carbamoyl-2′-deoxyuridine (7) were thermally stabilized about 3°C per modification and were about 160 times more stable to hydrolysis by snake venom phosphodiesterase (a 3′-exonuclease) than unmodified ODNs, but not by endonucleases. On the other hand, ODNs containing 4′-C-(aminoethyl)thymidine (14b), which was synthesized by a newly developed radical cyclization-ring-enlargement reaction by us, were 87 times more stable to hydrolysis by DNase I (an endonuclease) and 133 times more stable in 50% human serum than unmodified ODNs. The highly stereoselective synthesis of 4′-thioribonuclesides (^SNs) was also developed using a Pummerer reaction. Human thrombin RNA aptamer (CII-1-37) containing 4′-thiouridine and 4′-thiocytidine was obtained by SELEX with a K_d value of 4.7 nM, while a previously known RNA aptamer (RNA-24) has a K_d value of 85 nM. Studies of the modification pattern-RNAi activity relationships by using ^SNs have been carried out against luciferase genes. We found that siRNAs, which have 4 residues of ^SNs on both ends of the sense strand and 4 residues on the 3′-end of the antisense strand, were the most effective. 4′-ThioRNA is about 1100 times more stable in 50% human plasma than unmodified RNA. However, oligoribonucleotides (^SMONs) containing 2′-O-methyl-4′-thioribonucleosides were 9800 times more stable in 50% human plasma than unmodified RNA. Since ^SMON duplexes were thermally more stable than unmodified ON duplexes, therefore they would be quite suitable to use for oligonucleotide therapeutics.