Editorial [Hot Topic: Delivery, Intracellular Trafficking, and Biological Effectiveness of Oligonucleotide-Based Therapeutics Executive Editor: A. Mescalchin and G. Sczakiel]

Oligonucleotide-based therapeutic drugs of current interest include tools related to RNA interference (RNAi) such as short interfering RNA (siRNA), short hairping RNA (shRNA), or micro RNA (miRNA) as well as catalytic RNA and antisense oligonucleotides (asON). Based on resolved molecular patho-mechanisms of diseases and the causative involvement of genes in the development of diseases, their advantages include the mechanistic level of action, i.e. their ability to interfere with gene expression. On the technical level, challenges of the use of therapeutic oligonucleotide-based drugs include their delivery into target organs or tissues, their cellular uptake, the mode of their intracellular transport and their sub-cellular localization. All of those issues need to be successfully solved before their therapeutic application can be considered as sufficiently effective, i.e. before target suppression can be achieved at appropriate expense and realistic doses of the drug. Meanwhile it is obvious that the cellular delivery and the intracellular trafficking of oligomeric nucleic acid-based tools represent major technical hurdles for their successful therapeutic application. We feel that major new mechanistic insights are necessary before those steps of intracellular translocation of siRNA and/or components of RISC can be identified that are limiting in case of insufficient siRNA-induced target suppression. The cellular uptake and intracellular transport pathways as well as their underlying mechanisms need to be revealed before the technical hurdle of limited delivery and intracellular release can be conceivably addressed on a more rational basis. While the mode of action of various classes of transfectants and non-viral vector systems for oligonucleotide-based drugs seems to be largely enlightened, there is not much known on their intracellular fate. As a consequence, more quantitative methodology needs to be established in order to monitor trans-membrane transport as well as intracellular localization and mobility of siRNA as a function of their mode of delivery. Most promising approaches seem to be related to the intersection of molecular medicine, cell biology, biochemistry, biophysics, and chemistry. This view is exemplified by the collection of articles in this special issue which presents some of those interdisciplinary approaches. It provides a summary of major technologies related to the efficient cellular delivery of nucleic acid-based therapeutics. It also summarizes new methodology and new biological insights underlying the cellular and sub-cellular transport of oligonucleotides aiming their therapeutic application in vivo. Successful pre-clinical and clinical studies in the use of oligonucleotide-based therapeutics including asON and siRNA crucially rely on efficient delivery into target cells and target tissues. A comprehensive introduction into the various options for the cellular delivery of chemically synthesized siRNA by non-viral vector systems which include encapsulation, complex formation and conjugation of the cargo/siRNA is provided by Aigner in the first article of this special issue [1] who further includes an up-to-date list of in vivo studies in the use of formulated siRNA. Modes of administration of siRNA range from systemic and intravenous delivery to intra-tumoral, intra-thecal, nasal, and other local and applications. While systemic administration is commonly believed to deliver siRNA to a few sites and organs in vivo, local administration is thought to provide greater chances for a successful therapeutic delivery. One such example is the lung to which oligonucleotide-based drugs can be locally and topically delivery by nasal administration. Further, the lung as a target organ provides a very large and easily accessible surface for topical delivery of asON and siRNA and it is noteworthy that in a number of cases the use of transfectants could be omitted. Biological and technical characteristics of this target organ are summarized by Moschos et al. [2] who also provide a summary of past and ongoing in vivo studies in the use of asON and siRNA.