Next-Generation Lipids in RNA Interference Therapeutics

Abstract

RNA is emerging as a potential therapeutic modality for the treatment of incurable diseases. Despite intense research, the advent to clinical utility remains compromised by numerous biological barriers, hence, there is a need for sophisticated delivery vehicles. In this aspect, lipid nanoparticles (LNPs) are the most advanced platform among nonviral vectors for gene delivery. In this review, we critically review the literature and the reasons for ineffective delivery beyond the liver. We discuss the toxicity issues associated with permanently charged cationic lipids and then turn our attention to next-generation ionizable cationic lipids. These lipids exhibit reduced toxicity and immunogenicity and undergo ionization under the acidic environment of the endosome to release the encapsulated payload to their site of action in the cytosol. Finally, we summarize recent achievements in therapeutic nucleic acid delivery and report on the current status of clinical trials using LNP and the obstacles to clinical translation.

A Combinatorial Library of Lipid Nanoparticles for RNA Delivery to Leukocytes

“…These results demonstrated that ethanolamine and hydroxylamine linkers are more efficient dominators compared to hydrazine linkers in gene silencing. These results are supported by previous work demonstrating that LNPs showing surface p K a value of 5.5 to 7.0 exhibiting efficient in vivo gene silencing . We measured the p K a values of lipid‐2, lipid‐6, lipid‐8, and lipid‐10 LNPs (Figure S8, Supporting Information).…”

“…However, siRNAs are unable to cross the cell membrane due to their polyanionic nature, therefore suitable delivery strategies are required to access the target cell cytoplasm . Nonviral gene therapy is the most promising strategy to deliver nucleic acids with less or no immunogenic responses compared to viral gene delivery . Lipid nanoparticles (LNPs) containing ionizable amino lipids are the most advanced nonviral delivery platforms for negatively charged nucleic acids .…”

“…Nonviral gene therapy is the most promising strategy to deliver nucleic acids with less or no immunogenic responses compared to viral gene delivery . Lipid nanoparticles (LNPs) containing ionizable amino lipids are the most advanced nonviral delivery platforms for negatively charged nucleic acids . Ionizable amino lipid is a critical component of LNPs functionality.…”

“…We specifically concentrated on designing new lipids for in vivo delivery of RNAi payloads into hard‐to‐transfect cells, such as leukocytes. Previous generations of active ionizable lipids vary only in the linker region, but greatly influenced the in vivo efficiency in hepatic cells . To this end, using a rational approach, we designed a new class of amino lipid molecules containing hydrazine, hydroxylamine, or ethanolamine as a linker backbone.…”

Liposome Crosslinked Polyacrylamide/DNA Hydrogel: a Smart Controlled‐Release System for Small Molecular Payloads

“…Formed by assembly of lipids in aqueous solution, [11] liposomes have long been a scientific curiosity not only as model systems for understanding the cell membrane systems, [12] but also due to their capability to encapsulate hydrophobic or hydrophilic active molecules as microcarriers in drug delivery, gene therapy, and sensing. [13][14][15][16] Vesicle polymer gel forms by mixing vesicles solution with water-soluble polymer bearing hydrophobic motifs, with the vesicles serving as multivalent crosslinkers to bridge the adjacent polymer chains. [17,18] The hydrophobic effect is the main driven force in the solution-to-gel process, and the dynamic crosslinking may facilitate the formation of injectable hydrogels which are highly important in many biomedical applications.…”