Click chemistry of alkyne-modified RNA with different receptor ligand azides was used to prepare 3'-folate, 3'-cholesterol, and, as a new entity, 3'-anandamide-modified RNA in high yields and excellent purity. The anandamide-modified RNA shows surprisingly high transfection properties and enables the delivery of siRNA even into difficult-to-transfect RBL-2H3 cells which model neuronal uptake. Furthermore, the system was employed in human immune cells (BJAB), demonstrating silencing effects similar to those of a cationic, benchmark transfection reagent. In addition, the anandamide conjugates were found to be nontoxic. The reported chemistry and the described properties of the anandamide siRNA extend the possibilities of using siRNA-based gene silencing in neuronal and immune cells.

We report the development of dendritic siRNA nanostructures that are able to penetrate even difficult to transfect cells such as neurons with the help of a special receptor ligand. The nanoparticles elicit strong siRNA responses, despite the dendritic structure. An siRNA dendrimer directed against the crucial rabies virus (RABV) nucleoprotein (N protein) and phosphoprotein (P protein) allowed the suppression of the virus titer in neurons below the detection limit. The cell-penetrating siRNA dendrimers, which were assembled using click chemistry, open up new avenues toward finding novel molecules able to cure this deadly disease.

Wir berichten über die Entwicklung von dendritischen siRNA-Nanostrukturen, die das Einbringen von siRNA in schwierig zu transfizierende Zellen wie Neuronen mithilfe eines speziellen Rezeptorliganden ermçglichen. Die Nanopartikel rufen trotz ihrer dendritischen Struktur eine starke siRNA-Antwort hervor. Durch siRNA-Dendrimere gegen das Nukleoprotein (N-Protein) und das Phosphoprotein (P-Protein), zwei Schlüsselproteine des Tollwutvirus (RABV), konnte der Virustiter in Neuronen unter die Nachweisgrenze gesenkt werden. Die mithilfe von Klick-Chemie aufgebauten siRNADendrimere weisen den Weg für eine neuartige Heilungsmçglichkeit dieser tçdlichen Krankheit.