Abstract
Oligonucleotides have shifted drug discovery into a new paradigm due to their ability to silence the genes and inhibit protein translation. Importantly, they can drug the un-druggable targets from the conventional small-molecule perspective. Unfortunately, poor cellular permeability and susceptibility to nuclease degradation remain as major hurdles for the development of oligonucleotide therapeutic agents. Studies of safe and effective delivery technique with lipid bioconjugates gains attention to resolve these issues. Our review article summarizes the physicochemical effect of well-studied hydrophobic moieties to enhance the cellular entry of oligonucleotides. The structural impacts of fatty acids, cholesterol, tocopherol, and squalene on cellular internalization and membrane penetration in vitro and in vivo were discussed first. The crucial assays for delivery evaluation within this section were analyzed sequentially. Next, we provided a few successful examples of lipid-conjugated oligonucleotides advanced into clinical studies for treating patients with different medical backgrounds. Finally, we pinpointed current limitations and outlooks in this research field along with opportunities to explore new modifications and efficacy studies.
Highlights
Hydrophobic modifications such as cholesterol, fatty acid, α-tocopherol, and squalene still have room to mature compared to medicinal nanoformulation such as micelle, lipoplex, or, even, LNP
The primary goal of bioconjugation is elevating hydrophobic profile of ON-based therapy but a deeper quantitative understanding of structure related to delivery efficacy is still underappreciated
Additional structural explorations would lead to better optimization for highly stable and selective modified ON; current drawbacks in pharmacokinetic and biodistribution can be properly addressed
Summary
Oligonucleotide (ON) is a short strand of nucleic acid polymers mostly comprising of thirteen to twenty-five nucleotides, which can hybridize to targeted DNA or RNA. ONs are preferable therapeutic strategies to prevent and treat various disorders via selective inhibition of deleterious gene expression. It is shifting the era of drug discoveries into an exciting new field—oligonucleotide therapy. Chemical conjugation to neutral lipid/hydrophobic moiety can overcome this backlash. These naturally occurring biomolecules that are familiarized with the human system can reduce the risk of toxicity while enhancing cellular penetration and systemic stability. Additional discussion about potential therapeutic application and future outcomes of lipid-conjugated oligonucleotides will be highlighted
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