Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, 63090 Novosibirsk, Russia  
Tropical Biosphere Research Center, University of the Ryukyus, Okinawa 903-0213, Japan; [EMAIL_ADDRESS]  
Slokhov Institute of Science and Technology, Innovation Centre Skolkov, 121205 Moscow, Russia; [EMAIL_ADDRESS]  
[PERSON]  
1 Department of Chemistry, Lomonosov Moscow State University, 119991 Moscow, Russia  
Tropical Biosphere Research Center, University of the Ryukyus, Okinawa 903-0213, Japan; [EMAIL_ADDRESS]  
Slokhov Institute of Science and Technology, Innovation Centre Skolkov, 121205 Moscow, Russia; [EMAIL_ADDRESS]  
[PERSON]  
1 Department of Physics, Novosibirsk State University, 630090 Novosibirsk, Russia; [EMAIL_ADDRESS] (A.D.); [PERSON]S] (A.F.) Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia; [PERSON]_ADDRESS] (O.M. ); [EMAIL_ADDRESS] (M.Z.) Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, 63090 Novosibirsk, Russia  
Tropical Biosphere Research Center, University of the Ryukyus, Okinawa 903-0213, Japan; [EMAIL_ADDRESS]  
Slokhov Institute of Science and Technology, Innovation Centre Skolkov, 121205 Moscow, Russia; [EMAIL_ADDRESS]  
[PERSON]  
1 Department of Physics, Novosibirsk State University, 630090 Novosibirsk, Russia; [EMAIL_ADDRESS] (A.D.); [EMAIL_ADDRESS] (A.F.) Institute of Chemical Biology and Fundamental Medicineincluding biomolecules such as cholesterol,tocopherol (vitamin E) or fatty acids, and their synthetic analogues such as, e.g., DOTMA [19] have been shown to improve cellular uptake of oligonucleotides, most relevantly, in the form of lipid-oligonucleotide conjugates (LONs) [20; 21; 22]. In particular, lipid conjugates of antisense oligonucleotides and siRNAs have improved transfection ability and extended half-life in the bloodstream with beneficial impact on therapeutic activity in vivo [23; 24; 25]. We describe herein a series of novel DNA and RNA lipid conjugates, which have been chemically modified by one to four long-chain _N_-(sulfonyl)phosphoramide groups, namely, [(4-dodecylphenyl)sulfonyl]-phosphoramide group (\(\updelta\)) or (hexadecylsulfonyl)phosphoramide group (\(\upeta\)) at the internucleotide position(s) near the 3\({}^{\prime}\)- or 5\({}^{\prime}\)-end of the oligonucleotide chain (Figure 1). The oligonucleotides were obtained by an automated phosphoramidite solid-phase synthesis protocol that employs the Staudinger reaction between the support-bound phosphite triester and the respective sulfonyl azide instead of usual aqueous iodine oxidation to introduce either of the lipophilic modifications following a previously developed procedure [26; 27; 28]. The obtained lipid conjugates of oligodeoxyribonucleotides with one or two of the respective hydrophobic groups were nearly non-cytotoxic for either murine or human macrophages up to 20 uM concentration. Both types of lipid conjugates were able to enter the cells in a carrier free manner. Both features are beneficial for potential therapeutic application. The corresponding lipid conjugates of siRNAs with either two or four hydrophobic groups were designed to downregulate a validated target in multiple sclerosis, namely, repulsive guidance molecule a (RGMa) [29]. The conjugates with two groups were shown to possess silencing ability comparable to the unmodified siRNA when delivered by lipofectamine. This type of lipid conjugate may represent a useful addition to the inventory of therapeutic oligonucleotide derivatives.