Abstract: The present invention relates to modified oligonucleotides of 5-50 nucleotide residues, wherein at least 25% of the nucleotides are independently modified at the 2? position to comprise the structure of formula (I), wherein base is a purine or pyrimidine moiety; and R1, R2, R3, R4, p and q are as defined in the description. The modified oligonucleotides comprising said structures are useful as medicaments for enhancement of drug uptake in oligonucleotide based therapy in humans and animals.

Abstract: The use of at least one nucleic acid based nuclear localization signal including a natural or synthetic m3G-CAP is shown to increase transmembrane transport of a molecular cargo, in particular large molecules, into the nucleus. The use of natural and synthetic m3G-CAP is disclosed and the effect shown with a natural RNA 5? end nuclear localization signal composed of a 2,2,7-trimethylguanosine CAP (m3G-CAP) coupled to fluorescent Streptavidin in one example, and an antisense oligonucleotide in another. A methylenephosphonate modified m3G-CAP is shown to have improved stability in human serum and in cytosolic extract.