Systemic Delivery of Small Interfering RNA Therapeutics: Obstacles and Advances

Abstract

RNA interference (RNAi) has emerged as a critical tool for genetic therapeutics. Within the last two decades, there have been extensive investigations in the systemic delivery of these drugs but the obstacles in in vivo delivery have possessed a great difficulty in their administration. These developments led to the advances in systemic administration with designing and incorporation of various drug carriers, including bioconjugate systems, polymeric complexes, organic and inorganic nanoparticles. However, successful translation of these drug delivery systems for the clinical application has still been a great setback for these class of pharmaceutics. In order to improve their competency and applicability, systemic evaluation of currently available carrier systems is required. In this review, we focus on the obstacles in the systemic administration of small interfering RNAs (siRNAs) and the advances with various carrier systems to overcome the limitations of these obstacles. General obstacles in siRNA delivery have been discussed with major emphasis on the barriers at different stages of systemic administration. Then, advances in their application for targeted delivery with rationally designed carrier systems such as bioconjugates, polymeric complexes, and nanoparticles have been introduced. Lastly, we discuss the progress and state of clinical studies of siRNA therapeutics with perspectives of clinical potential.

Design, synthesis and evaluation of novel, branched trident small interfering RNA nanostructures for sequence-specific RNAi activity

“…[10][11][12][13][14] Our review on the systemic delivery of siRNAs has also enlightened several delivery carriers such as lipid nanoparticles, cell penetrating peptides, aptamers, lipid bioconjugates and dendrimers for the targeted delivery. 15 However, a self-assembled delivery system with branched RNA structure has not yet been exploited to facilitate the efficient delivery and silencing activity. Large molecular size of such self-assemblies will also assist in evading the ltration through the glomerulus.…”

Novel Convenient Approach to the Solid-Phase Synthesis of Oligonucleotide Conjugates

“…The key point upon the design of oligonucleotide therapeutics and probes is the proper choice of linker between the oligonucleotide and functional moiety, such as delivery agent, fluorophore, or other reporter groups [8,18,40,41]. Our method permits varying the size and structure of the linker to optimize its length and stability for the particular task.…”

A Review of Protein- and Peptide-Based Chemical Conjugates: Past, Present, and Future

“…Nonetheless, recent medicinal chemistry advances, along with expansion of oligonucleotide formats, have renewed the excitement in their potential once again [ 48 , 49 , 50 ]. Because an intravenously dosed oligonucleotide must overcome numerous biological barriers in order to reach its intracellular target, it is not surprising that many of the clinically advanced or approved oligonucleotides are either leveraging alternative administration routes such as subcutaneous (SC), intrathecal (IT), and intravitreal (ITV) injection [ 50 ] or are being paired with a delivery strategy for intravenous delivery (IV) ( Figure 2 A) [ 51 , 52 , 53 ]. Thus, more recently, the focus of oligonucleotide development has expanded to include therapeutic delivery, in addition to oligonucleotide design considerations.…”