Enhanced understanding of the RNA interference (RNAi) process creates novel medical opportunities. The human genome encodes more than 1700 microRNAs (miRs), which are expressed in a tissue-and disease-dependent manner. Transcribed miR undergoes a maturation process, with a 21–23 nucleotides containing RNA guide strand incorporated together with argonaute protein into an RNA-induced silencing complex (RISC). RISCs recognize complementary messenger RNA (mRNA) strands by Watson–Crick base pairing (perfect match in the first seven or eight nucleotides at the 5о end of the guide strand) and block the translation of mRNA into a protein (Scheme 1). Thus, the expression of genes is regulated on the posttranscriptional level. The dysregulation of miR expression has been associated with human diseases. In cancer, the loss of tumor suppressor miRs (such as miR-34) results in more aggressive, metastatic, or chemoresistant tumor cells. The therapeutic re-introduction of suppressor miRs into tumors (Scheme 1, route 1) may reverse the malignant phenotypes. The clinical development of an miR-34 mimic (as lipid-based formulation) is ongoing for patients suffering from liver cancer or liver metastasis.[1] Conversely, other miRs, so-called onco-miRs, promote tumor growth and aggressiveness. Such onco-miRs can be inactivated by specific base pairing with antisense molecules (8–23 nucleotides), termed miR antagonists (anti-miRs, Scheme 1, route 2), thus recovering benign protein expression profiles.[2] The number of miR and related RNAi therapeutics in clinical testing is steadily increasing.[3] Intracellular delivery, ideally in a tissue-targeted manner, is the key limitation to further progress. RNA degrades in a biological environment and, as a medium-sized polyanion, cannot diffuse passively into cells. In order to solve this problem, several chemical strategies are currently being evaluated, including 1) chemical backbone modifications, 2) nanoparticle formulations, and 3) oligonucleotide conjugates. Chemical modifications have been introduced to directly stabilize oligonucleotide backbones. They include peptide nucleic acid (PNA), locked nucleic acid (LNA), or tricycloDNA chemistry.[4] To facilitate the cellular uptake, sequences were minimized with regard to the number of nucleotides, resulting in potent single stranded siRNAs or tiny LNAs. Alternatively, inspired by the delivery of natural viruses, RNAi molecules have been incorporated into virus-like nanoparticles. These utilize cell binding and other transport domains for targeted intracellular delivery. A third strategy takes advantage of both foregoing strategies: oligonucleotides with improved chemical backbones have been conjugated with small transport domains. They include receptor-targeting ligands for cell binding or cell-penetrating peptides for crossing cell-surface or endosomal membranes.[5] These conjugates may target specific sites and, as a result of their smaller size, are more likely to diffuse into target tissues compared with larger nanoparticles. For example, the subcutaneous injection of siRNA, conjugated with synthetic trimeric N-acetyl-galactosamine ligand targeted to the asialoglycoprotein receptor of liver cells, resulted in very promising gene silencing in mice [6] and men.[3] For many RNAi drug delivery approaches, the liver turned out to be the most amenable target organ. Systemic targeting of other tissues had been less successful. Debates on the most productive cell-entry mechanism (by directly crossing the