Overcoming the delivery barrier of oligonucleotide drugs and enhancing nucleoside drug efficiency: The use of nucleolipids

Abstract

With the rapid development of synthetic technology and biological technology, many nucleic acid‐based drugs have entered the clinical trials. However, their inherent disabilities in actively and efficiently penetrating cell membranes still severely restrict their further application. The main drawback of cationic lipids, which have been widely used as nonviral vectors of nucleic acids, is their high cytotoxicity. A series of nucleoside‐based or nucleotide‐based nucleolipids have been reported in recent years, due to their oligonucleotide delivery capacity and low toxicity in comparison with cationic lipids. Lipophilic prodrugs of nucleoside analogs have extremely similar structures with nucleolipid vectors and are thus helpful for improving the transmembrane ability. This review introduces the progress of nucleolipids and provides new strategies for improving the delivery efficiency of nucleic acid‐based drugs, as well as lipophilic prodrugs of nucleosides or nucleotides for antiviral or anticancer therapies.

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

“…They can selfassemble or encapsulate oligonucleotides through nucleobase interaction. To avoid the toxicity invoked by using of cationic lipids, the interactions between nucleobases, such as π-stacking, which is a special interaction to lead formation of DNA helix structure and hydrogen bonding, were used to form nucleic acid lipid nanoparticles (Zhou et al, 2020b). To increase the half-life time and avoid nonspecific interaction, PEG was incorporated in this system.…”

Progress in the molecular pathogenesis and nucleic acid therapeutics for Parkinson's disease in the precision medicine era

“…Potent nucleic acid delivery systems are also needed to ensure effective cell uptake or even tissue‐specific delivery to allow for better assessment of therapeutic benefits. Various approaches, especially bioconjugates including cholesterol, cell‐penetrating peptides, nucleolipids, receptor ligands, and antibodies have been proposed to enhance nucleic acids delivery, 171–174 however even those approaches have limitations including immunogenic consequences and lack of efficiency and specificity 175 . To date, N ‐acetylgalactosamine (GalNac) appears to be the most potent conjugate for siRNA delivery that specifically targets hepatocytes with limited off‐target effects 176,177 .…”

Rational preparation and application of a mRNA delivery system with cytidinyl/cationic lipid

“…Other than the classical amphiphilic lipids, they are constructed with a highly specialized polar head group (adenosine, thymidine, cytidine, guanosine, uracil, or their analogs), facilitating additional hydrogen bonding with complementary nucleobases via Watson-Crick base paring and π-stacking, and spontaneously, these lipids self-assemble in water with low toxicity and immunogenicity [ [16] , [17] , [18] , [19] , [20] ]. A series of similar amphiphilic nucleoside-based lipids have been devised as carriers for nucleic acid drugs [ 20 , 21 ]. The nucleotide moiety promoted the transfection efficacy, where the cationic nucleoside-based lipid, [Tosylate salt of 1′-(2′,3′-dioleyl-5′-trimethylammonium-α, β-D-ribofuranosyl)-3-nitropyrrole] (TRN), significantly enhanced siRNA permeation to silence the expression upon mouse fibroblas (NIH 3 T3) at N/P ratio of 10 [ 22 ].…”