Delivery systems and local administration routes for therapeutic siRNA

Abstract

With the increasing number of studies proposing new and optimal delivery strategies for the efficacious silencing of gene-related diseases by the local administration of siRNAs, the present review aims to provide a broad overview of the most important and latest developments of non-viral siRNA delivery systems for local administration. Moreover, the main disease targets for the local delivery of siRNA to specific tissues or organs, including the skin, the lung, the eye, the nervous system, the digestive system and the vagina, were explored.

Fig. 1

Mechanisms of RNA interference. Initiation Phase: generation of effectors molecules. Nucleus: micro-RNA (miRNA) synthesis. miRNA gene is transcript by RNA Pol II/III forming miRNA primary (pri-miRNA), which is processed by Drosha and DGCR8 in miRNA precursor (pre-miRNA). pre-miRNA is exported by exportin-5 to cytoplasm. Cytoplasm: dsRNA and pre-miRNA are processed by Dicer in siRNA and miRNA, respectively. Execution Phase: incorporation of effectors molecules in protein complexes and promotion of gene silencing. siRNA or miRNA binds to RISC (RNA induced silencing complex—composed by Dicer, TRBP and Ago2). siRNA or miRNA strands are separated. Antisense strand remains bound to RISC complex, which is activated and guided to the target mRNA. The complex siRNA/RISC associates with the target mRNA promotes its degradation. The complex miRNA/RISC associates with the target mRNA promotes its degradation or translational repression, depending of the level of the complementarity.

Fig. 2

Schematic representation of different non-viral vectors used for siRNA delivery. Polymer-, lipid-, peptide- or protein-based systems form complexes, usually through the spontaneous electrostatic interactions, with siRNA which can be both entrapped within the core or adsorbed onto the surface of the carrier. Multifunctional nanocarriers combining several useful properties in one particle that have been developed to enhance the siRNA delivery.

Fig. 3

Physical methods for siRNA delivery in the skin. In the iontophoresis (a) the positively charged chamber releases the formulation with the same charge through electromigration and electroosmosis. In the gene gun (b) an adjustable low-pressure helium pulse impel the gene-coated gold particles into the target. The electroporation (c) uses electric pulses to create transient pores in a cell membrane and the ultrasound (d) alters the permeability properties of the cell membrane improving local siRNA delivery.