Lipid-based Nanocarriers for siRNA Delivery: Challenges, Strategies and the Lessons Learned from the DODAX: MO Liposomal System

Abstract

The possibility of using the RNA interference (RNAi) mechanisms in gene therapy was one of the scientific breakthroughs of the last century. Despite the extraordinary therapeutic potential of this approach, the need for an efficient gene carrier is hampering the translation of the RNAi technology to the clinical setting. Although a diversity of nanocarriers has been described, liposomes continue to be one of the most attractive siRNA vehicles due to their relatively low toxicity, facilitated siRNA complexation, high transfection efficiency and enhanced pharmacokinetic properties. </P><P> This review focuses on RNAi as a therapeutic approach, the challenges to its application, namely the nucleic acids’ delivery process, and current strategies to improve therapeutic efficacy. Additionally, lipid-based nanocarriers are described, and lessons learned from the relation between biophysical properties and biological performance of the dioctadecyldimethylammonium:monoolein (DODAX: MO) system are explored. </P><P> Liposomes show great potential as siRNA delivery systems, being safe nanocarriers to protect nucleic acids in circulation, extend their half-life time, target specific cells and reduce off-target effects. Nevertheless, several issues related to delivery must be overcome before RNAi therapies reach their full potential, namely target-cell specificity and endosomal escape. Understanding the relationship between biophysical properties and biological performance is an essential step in the gene therapy field.

Targeting circular RNAs as a therapeutic approach: current strategies and challenges

“… 2 Importantly, nanoparticle delivery can overcome many limitations of RNAi molecules by protecting them from degradation, facilitating cellular uptake, and preventing immune activation. 30 – 32 , 144 – 146 …”

“…Our lab has been using gold nanoparticles (AuNPs) as a delivery system in animal studies because they are highly stable, pure, and their surface is easy to modify. 144 , 147 We delivered AuNPs conjugated with siRNA targeting circDnmt1 or AON targeting binding sites on circDnmt1 for Auf1 and p53 proteins as a therapeutic approach for breast cancer. 15 We found that both treatments suppressed cellular autophagy and tumor growth and extended the lifespan of mice.…”

Rationale and Application of PEGylated Lipid-Based System for Advanced Target Delivery of siRNA

“…Lipid nanoparticles (LNPs) which contain siRNA and ionizable cationic lipids have proven to be effective in delivering gene materials to target sites. Some of them were proven to be effective in clinical trials (Oliveira et al, 2019;Xin et al, 2019). The ionizable cationic lipids such as heptatraconta-6,9,28,31-tetraene-19-yl 4-(dimethylamino) butanoate (Dlin-MC3-DMA) could provide a mechanism (acid dissociation constants below seven) to positively charge at low pH to entrap siRNA and keep neutral surface charges during circulation.…”

“…The toxicity of the lipid-based nanoparticles for delivery of siRNA is critical to turn research work to clinical applications. The toxicity of the lipid-based nanoparticles for siRNA delivery is mainly caused by usage of cationic lipids and also the immune response from siRNA (Tan, 2001;Bridge et al, 2003;Sledz et al, 2003;Soenen et al, 2009;Oliveira et al, 2019). siRNA can induce immune response to trigger interferon and inflammatory effect by the toll-like receptors (TLRs) such as TLR3 and TLR7, and the use of lipid-based nano vector may accelerate this activation to evoke unwanted side effects (Dass, 2002;Hornung et al, 2005;Kleinman et al, 2008).…”

Graphene-Based Nanosystems: Versatile Nanotools for Theranostics and Bioremediation

“…Gene therapy requires the incorporation of genes, gene segments or oligonucleotides in nanocarriers that provide protection against enzyme-induced degradation and/or inactivation of the genetic material [8,87]. When used in cancer, the mechanism of action of this therapeutic strategy is based on: (i) deactivation of oncogenes; (ii) substitution of non-functioning tumor suppressor genes; (iii) inducing cell death or repair of normal cell function; (iv) defense of normal cells from drug-induced toxicity or activation of immune cells for the destruction of cancer cells [8,87]. The same favorable properties of GBNs for chemotherapy are valid for explaining their use in gene therapy.…”