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

Abstract

RNA interference (RNAi) technology has become a powerful tool in application of unraveling the mechanism of disease and may hold the potential to be developed for clinical uses. Small interfering RNA (siRNA) can bind to target mRNA with high specificity and efficacy and thus inhibit the expression of related protein for the purpose of treatment of diseases. The major challenge for RNAi application is how to improve its stability and bioactivity and therefore deliver therapeutic agents to the target sites with high efficiency and accuracy. PEGylated lipid-based delivery system has been widely used for development of various medicines due to its long circulating half-life time, low toxicity, biocompatibility, and easiness to be scaled up. The PEGylated lipid-based delivery system may also provide platform for targeting delivery of nucleic acids, and some of the research works have moved to the phases for clinical trials. In this review, we introduced the mechanism, major challenges, and strategies to overcome technical barriers of PEGylated lipid-based delivery systems for advanced target delivery of siRNA in vivo. We also summarized recent advance of PEGylated lipid-based siRNA delivery systems and included some successful research works in this field.

Specific delivering of RNAi using Spike's aptamer‐functionalized lipid nanoparticles for targeting SARS‐CoV‐2: A strong anti‐Covid drug in a clinical case study

“…Similarly, intranasally administered RNAi was indicated to reduce or inhibit the viral activity of para‐influenza virus up to 99% (Bitko et al, 2005 ). Intranasal administration of two RNAi duplexes targeting ORF1b and spike coding regions of SARS‐CoV were resulting in diminished SARS‐CoV titer, reduced fever, and reduced diffuse alveoli damage (Ge et al, 2021 ). Appropriately aptamer‐modified nanoparticles provide immunologically inert‐surfaces contact with the human system in addition to possessing the high retention efficiency and permeability to enhance their deposition and efficacy in targeted tissues.…”

“…In this method, RNAi molecules were encapsulated by using lipid‐based nanoparticles, which provide more stability and well penetration to target tissue (Ge et al, 2021 ; Saw & Song, 2019 ).…”

Pre-clinical non-viral vectors exploited forin vivoCRISPR/Cas9 gene editing: an overview

“…119 PEGylated lipids are arrayed on the outer layer to reduce LNPs aggregation and opsonization in the bloodstream. 120 A number of studies have employed LNPs for the delivery of CRISPR plasmids to disrupt different genes (Nf1, CD80, CD86, CD40, Plk1, BCR-ABL, DNMT1) and have significantly enhanced the therapeutic outcomes in animal models for type 1 and 2 diabetes (T1D, T2D), 88,90,95 melanoma, 87 chronic leukaemia 91 and ovarian cancer. 121 While promising, plasmid delivery, like viral vectors, still carries a risk of genomic integration, as well as immunogenicity, this has shifted the attention towards developing RNA-based gene editing (Cas9 mRNA/ sgRNA) approaches.…”

“…119 PEGylated lipids are arrayed on the outer layer to reduce LNPs aggregation and opsonization in the bloodstream. 120…”

Evolution of complexity in non-viral oligonucleotide delivery systems: from gymnotic delivery through bioconjugates to biomimetic nanoparticles

“…Complement activation is a frequent reaction to RNA therapeutics, therefore development of strategies to avoid immune response are crucial. A common strategy for LNPs is to conjugate polyethylene glycol polymer (PEG) to the surface of nanoparticles or addition of PEGylated lipids to LNP formulations[ 24 ]. PEG prevents opsonization and recognition by macrophages leading to higher stability, longer circulation times and lower immune response[ 25 ].…”