Stable RNA nanoparticles as potential new generation drugs for cancer therapy

Abstract

Human genome sequencing revealed that only ~1.5% of the DNA sequence coded for proteins. More and more evidence has uncovered that a substantial part of the 98.5% so-called “junk” DNAs actually code for noncoding RNAs. Two milestones, chemical drugs and protein drugs, have already appeared in the history of drug development, and it is expected that the third milestone in drug development will be RNA drugs or drugs that target RNA. This review focuses on the development of RNA therapeutics for potential cancer treatment by applying RNA nanotechnology. A therapeutic RNA nanoparticle is unique in that its scaffold, ligand, and therapeutic component can all be composed of RNA. The special physicochemical properties lend to the delivery of siRNA, miRNA, ribozymes, or riboswitches; imaging using fluogenenic RNA; and targeting using RNA aptamers. With recent advances in solving the chemical, enzymatic, and thermodynamic stability issues, RNA nanoparticles have been found to be advantageous for in vivo applications due to their uniform nano-scale size, precise stoichiometry, polyvalent nature, low immunogenicity, low toxicity, and target specificity. In vivo animal studies have revealed that RNA nanoparticles can specifically target tumors with favorable pharmacokinetic and pharmacodynamic parameters without unwanted accumulation in normal organs. This review summarizes the key studies that have led to the detailed understanding of RNA nanoparticle formation as well as chemical and thermodynamic stability issue. The methods for RNA nanoparticle construction, and the current challenges in the clinical application of RNA nanotechnology, such as endosome trapping and production costs, are also discussed.

Noncanonical Synthetic RNAi Inducers

“…Moreover, nanostructures of different shapes and sizes have been proposed as an effective delivery system for siRNA, ribozymes, etc. [106,107]. Recently, it has been demonstrated that branched small RNA structures may also be effective RNAi inducers.…”

“…Initially, branched oligonucleotides were applied to study mRNA splicing [102][103][104]. Then diverse branched structures were used as building blocks for self-assembling nanostructures [105][106][107]. Moreover, nanostructures of different shapes and sizes have been proposed as an effective delivery system for siRNA, ribozymes, etc.…”

“…Recently, it has been demonstrated that branched small RNA structures may also be effective RNAi inducers. Thus, these duplexes can simultaneously inhibit two or more genes and possess improved silencing activity and intracellular delivery properties [96][97][98][99][100][101][102][103][104][105][106][107][108][109]. Different strategies are developed to form branches.…”

Emerging role of microRNAs in the treatment of hepatocellular carcinoma

“…The main types of nanoparticles used for conveying siRNA and miRNA are cationic liposomes or positively charged polymers, such as polyethylenimine, or waterinsoluble polymers, such as poly-lactide-co-glycolide. 79 For example, in a diethylnitrosamine-induced HCC mouse model, systemic administration of miR-124 through liposomes led to a reduction in tumor growth and tumor size via induction of apoptosis and deregulation of an miRNA/inflammatory feedback loop circuit involving hepatocyte nuclear factor 4 alpha 80 (see Table 5 for a list of nanocarrier formulations used in miRNA delivery). Trang et al have used neutral lipid emulsions to mediate the delivery of miR-let-7 and miR-34a in a non-small cell lung cancer model.…”

Osteoprotective Properties of RNA-Containing Drug Osteochondrin S on the Model of Insufficiency of Sex Hormones in Rats

“…RNA-containing drugs can accelerate tissue regeneration upon damage, change the course of the inflammatory process, stimulate subpopulations of lymphocytes, enhance phagocytosis of macrophages and influence the body's responses to tumors and allografts (Afjeh et al, 2013;Dogini et al, 2014;Shu et al, 2014;Zeliadt, 2014). These effects of RNA-containing substances can be useful in correcting of age-associated conditions (Ni et al, 2011;Masuda et al, 2013).…”