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Updated: Jun 22, 2026
Intrathecal Delivery of Antisense Oligonucleotides in the Rat Central Nervous System
Published on: October 29, 2019
Oral delivery of siRNA and antisense oligonucleotides
1Department of Pharmacology and Toxicology, Faculty of Medicine, Health Sciences Center, Kuwait University, Safat, Kuwait. Saghir@hsc.edu.kw
Abstract:
Inhibition of gene expression with antisense oligonucleotides or RNA interference (RNAi) mediated gene silencing by small interfering RNA (siRNA) has tremendous potential to silence the expression of disease-causing genes in the clinic. A major hurdle to their widespread clinical use is the safe and efficient delivery to target cells in vivo. Delivery via the oral route is considered the holy grail for small molecule and macromolecular drug delivery as it has the advantages of ease of administration, increased patient compliance, and cost-effectiveness. However, the harsh biological milieu of the acidic stomach and enzyme-rich gastrointestinal tract make efficient delivery of oligonucleotides and siRNA via the oral route difficult. Nonetheless, the first studies on the oral delivery of siRNA in animals and antisense oligonucleotides in humans suggest that significant oral delivery of these nucleic acids can be achieved across the gut wall. This can occur either by encapsulating siRNA within biodegradable particles that protect them from degradation and target them to M cells in intestinal Peyer's patches or by using chemically stabilized antisense oligonucleotides together with a penetration enhancer. This article reviews these studies as they mark important advances in the delivery of gene silencing nucleic acids and have heralded a new wave of enthusiasm that might lead to a significant expansion of the therapeutic options available for gene silencing drugs in the clinic.
Insights
Oral delivery of gene silencing drugs like antisense oligonucleotides and small interfering RNA (siRNA) is challenging but achievable. Novel delivery methods show promise for in vivo gene silencing therapies.
Area of Science:
- Molecular Biology
- Pharmacology
- Drug Delivery Systems
Background:
- Antisense oligonucleotides and RNA interference (RNAi) mediated gene silencing using small interfering RNA (siRNA) offer potential for treating genetic diseases.
- Efficient and safe in vivo delivery of these nucleic acids remains a significant obstacle for clinical application.
- Oral drug delivery is highly desirable due to patient convenience and cost-effectiveness but faces challenges from the gastrointestinal environment.
Purpose of the Study:
- To review recent advances in the oral delivery of gene silencing nucleic acids.
- To highlight strategies overcoming the harsh gastrointestinal environment for oligonucleotide and siRNA delivery.
- To assess the potential impact of successful oral delivery on future gene silencing therapies.
Main Methods:
- Review of studies on oral delivery of siRNA in animal models.
- Review of studies on oral delivery of antisense oligonucleotides in human subjects.
- Analysis of delivery strategies including biodegradable particle encapsulation and chemical stabilization with penetration enhancers.
Main Results:
- Evidence suggests significant oral delivery of nucleic acids across the gut wall is possible.
- Biodegradable particles can protect siRNA from degradation and target Peyer's patch M cells.
- Chemically stabilized antisense oligonucleotides combined with penetration enhancers facilitate oral absorption.
Conclusions:
- Successful oral delivery of gene silencing nucleic acids is becoming a reality.
- These advancements pave the way for expanded therapeutic options using gene silencing drugs.
- Further research and development in oral delivery systems are crucial for clinical translation.
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