One aspect of the present invention relates to a double-stranded 
oligonucleotide comprising at least one non-natural 
nucleobase. In certain embodiments, the non-natural 
nucleobase is difluorotolyl, nitroindolyl, nitropyrrolyl, or nitroimidazolyl. In a preferred embodiment, the non-natural 
nucleobase is difluorotolyl. In certain embodiments, only one of the two 
oligonucleotide strands comprising the double-stranded 
oligonucleotide contains a non-natural nucleobase. In certain embodiments, both of the oligonucleotide strands comprising the double-stranded oligonucleotide independently contain a non-natural nucleobase. In certain embodiments, the oligonucleotide strands comprise at least one modified 
sugar moiety. Another aspect of the present invention relates to a single-stranded oligonucleotide comprising at least one non-natural nucleobase. In a preferred embodiment, the non-natural nucleobase is difluorotolyl. In certain embodiments, the 
ribose sugar moiety that occurs naturally in nucleosides is replaced with a 
hexose sugar, polycyclic heteroalkyl ring, or cyclohexenyl group. In certain embodiments, at least one 
phosphate linkage in the oligonucleotide has been replaced with a phosphorothioate linkage.