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Delivery of RNA Therapeutics: The Great Endosomal Escape!
Steven F Dowdy1, Ryan L Setten1, Xian-Shu Cui1
1Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, California, USA.
Abstract:
RNA therapeutics, including siRNAs, antisense oligonucleotides, and other oligonucleotides, have great potential to selectively treat a multitude of human diseases, from cancer to COVID to Parkinson's disease. RNA therapeutic activity is mechanistically driven by Watson-Crick base pairing to the target gene RNA without the requirement of prior knowledge of the protein structure, function, or cellular location. However, before widespread use of RNA therapeutics becomes a reality, we must overcome a billion years of evolutionary defenses designed to keep invading RNAs from entering cells. Unlike small-molecule therapeutics that are designed to passively diffuse across the cell membrane, macromolecular RNA therapeutics are too large, too charged, and/or too hydrophilic to passively diffuse across the cellular membrane and are instead taken up into cells by endocytosis. However, similar to the cell membrane, endosomes comprise a lipid bilayer that entraps 99% or more of RNA therapeutics, even in semipermissive tissues such as the liver, central nervous system, and muscle. Consequently, before RNA therapeutics can achieve their ultimate clinical potential to treat widespread human disease, the rate-limiting delivery problem of endosomal escape must be solved in a clinically acceptable manner.
Insights
RNA therapeutics offer targeted disease treatment but face delivery challenges. Overcoming cellular defenses, particularly endosomal entrapment, is crucial for unlocking their full clinical potential.
Area of Science:
- Biotechnology
- Molecular Biology
- Pharmacology
Background:
- RNA therapeutics, such as siRNAs and antisense oligonucleotides, show promise for treating diverse diseases by targeting RNA.
- Their mechanism relies on Watson-Crick base pairing, independent of protein structure.
- Evolutionary cellular defenses and the physical properties of RNA therapeutics hinder cellular entry and endosomal escape.
Purpose of the Study:
- To highlight the significant potential of RNA therapeutics in treating human diseases.
- To identify the primary obstacle preventing the widespread clinical application of RNA therapeutics.
- To emphasize the critical need for effective endosomal escape strategies.
Main Methods:
- Review of RNA therapeutic mechanisms and cellular uptake pathways.
- Analysis of endocytosis as the primary route for RNA therapeutic entry.
- Discussion of endosomal entrapment as a major barrier to therapeutic efficacy.
Main Results:
- RNA therapeutics are too large, charged, or hydrophilic for passive membrane diffusion.
- Endocytosis leads to entrapment within endosomes, with over 99% of therapeutics remaining trapped.
- This endosomal entrapment significantly limits the bioavailability and effectiveness of RNA therapeutics.
Conclusions:
- Effective endosomal escape is the rate-limiting step for RNA therapeutics.
- Solving the endosomal escape problem is essential for realizing the clinical potential of RNA-based medicines.
- Further research into clinically acceptable endosomal escape mechanisms is required.
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