Bioinspired Lipid Nanocarriers for RNA Delivery

Abstract

RNA therapy is a disruptive technology comprising a rapidly expanding category of drugs. Further translation of RNA therapies to the clinic will improve the treatment of many diseases and help enable personalized medicine. However, in vivo delivery of RNA remains challenging due to the lack of appropriate delivery tools. Current state-of-the-art carriers such as ionizable lipid nanoparticles still face significant challenges, including frequent localization to clearance-associated organs and limited (1–2%) endosomal escape. Thus, delivery vehicles must be improved to further unlock the full potential of RNA therapeutics. An emerging strategy is to modify existing or new lipid nanocarriers by incorporating bioinspired design principles. This method generally aims to improve tissue targeting, cellular uptake, and endosomal escape, addressing some of the critical issues facing the field. In this review, we introduce the different strategies for creating bioinspired lipid-based RNA carriers and discuss the potential implications of each strategy based on reported findings. These strategies include incorporating naturally derived lipids into existing nanocarriers and mimicking bioderived molecules, viruses, and exosomes. We evaluate each strategy based on the critical factors required for delivery vehicles to succeed. Finally, we point to areas of research that should be furthered to enable the more successful rational design of lipid nanocarriers for RNA delivery.

Synergistic vesicle-vector systems for targeted delivery

“…Exosomes act as carriers of RNA, lipids, and protein cargoes to alter the state of recipient cells [ 131 ]. Utilizing natural selective enrichment of the desired RNA into EVs is the primary objective of endogenous RNA loading [ 132 ]. Either a passive loading method or an active loading process can achieve this.…”

Bioinspired Approaches for Central Nervous System Targeted Gene Delivery

“…89,90 Golubovic et al, (2023), the authors describe a process where liposomes are employed as versatile nanocarriers for the efficient delivery of RNA molecules. 91 These liposomes are bioinspired, they are designed to mimic the natural lipid bilayers found in cell membranes. 92 Additionally, liposomes can be functionalized with specific ligands or peptides that enhance their cellular uptake and targeting abilities.…”

“…Golubovic et al, (2023), the authors describe a process where liposomes are employed as versatile nanocarriers for the efficient delivery of RNA molecules . These liposomes are bioinspired, they are designed to mimic the natural lipid bilayers found in cell membranes .…”

Rational design and combinatorial chemistry of ionizable lipids for RNA delivery

“…5,6 However, delivering these large, polyanionic molecules to the cytoplasm so that they can be translated remains a significant challenge. [7][8][9][10][11][12] Moreover, mRNA is highly unstable and prone to degradation by ubiquitous nucleases. [13][14][15][16][17][18] To address these issues, scientists have developed various non-viral synthetic nanoparticles for mRNA delivery, among which lipid nanoparticles (LNPs) are the most clinically viable.…”