Triggering RNAi with multifunctional RNA nanoparticles and their delivery

Abstract

Proteins are considered to be the key players in structure, function, and metabolic regulation of our bodies. The mechanisms used in conventional therapies often rely on inhibition of proteins with small molecules, but another promising method to treat disease is by targeting the corresponding mRNAs. In 1998, Craig Mellow and Andrew Fire discovered dsRNA-mediated gene silencing via RNA interference or RNAi. This discovery introduced almost unlimited possibilities for new gene silencing methods, thus opening new doors to clinical medicine. RNAi is a biological process that inhibits gene expression by targeting the mRNA. RNAi-based therapeutics have several potential advantages (i) a priori ability to target any gene, (ii) relatively simple design process, (iii) site-specificity, (iv) potency, and (v) a potentially safe and selective knockdown of the targeted cells. However, the problem lies within the formulation and delivery of RNAi therapeutics including rapid excretion, instability in the bloodstream, poor cellular uptake, and inefficient intracellular release. In an attempt to solve these issues, different types of RNAi therapeutic delivery strategies including multifunctional RNA nanoparticles are being developed. In this mini-review, we will briefly describe some of the current approaches.

Keywords: RNA interference; RNA nanoparticles; RNA nanotechnology; RNA/DNA hybrids; delivery; siRNA.

Figure 1.

Schematic representation of various exogenous RNAi activation pathways.

Figure 2.

Interferon (IFN)-activity experiments with THP-1 IFN reporter cells for functionalized RNA (1) and DNA (2) cubes described in Afonin et al. [90]. For IFN-activity experiments, THP-1 IFN reporter cells were depleted of cGAS (a DNA-binding receptor in the type I IFN signaling pathway) or MAVS (an RNA-induced stimulation of IFN activity) by specific siRNAs. Cells were transfected with nanocubes and secreted alkaline phosphatase activity was measured in culture supernatants 24 hours post-transfection.

Figure 3.

Various possible routes and some examples of carriers used for delivery of therapeutic RNAi inducers.

Figure 4.

Chemical structure of selected bolaamphiles GLH-19, 20, 58 and 60. Note the differences in the head groups and their placement relative to the ends of the central hydrophobic chain.