Click-Modified Anandamide siRNA Enables Delivery and Gene Silencing in Neuronal and Immune Cells

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.