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Oligonucleotide delivery: a cellular prospective
E Liang1, P S Ajmani, J A Hughes
1Department of Pharmaceutics, College of Pharmacy, University of Florida, USA.
Abstract:
The use of oligonucleotides (ONs) for gene therapy of certain diseases has been discussed since the late 1970s. ONs are single stranded chains of nucleic acids that can hybridize with target nucleic acid sequences to inhibit specific proteins, and therefore allow selective treatment of various diseases. The use of ONs is limited due to their instability in biological tissues and difficulty in delivery to the intracellular compartments of the cell. Chemical analog approaches have been used to address the instability issue and delivery systems have been developed to increase cellular uptake of ONs. It is generally thought that ONs with or without a delivery system are transported into cells by endocytosis, and then accumulate within endosomes where they are significantly inactivated. The rate and extent of movement of ON from endosomes appears to be important in determining ON effects. Consequently, developing accessory compounds or delivery methods that enhance endosome to cytoplasm transfer may be vital to ON therapy. This review focuses on investigating mechanisms of various delivery approaches at the cellular/intracellular level that have demonstrated utility in increasing ON activity or cellular accumulation. The future prospects of ON delivery are also addressed.
Insights
Oligonucleotides (ONs) show promise for gene therapy but face delivery challenges. Enhancing endosome to cytoplasm transfer is key to improving ON efficacy and cellular accumulation for better therapeutic outcomes.
Area of Science:
- Biochemistry
- Molecular Biology
- Gene Therapy
Background:
- Oligonucleotides (ONs) are single-stranded nucleic acids with therapeutic potential since the 1970s.
- ONs function by hybridizing to target nucleic acids, inhibiting specific protein production for disease treatment.
- Key limitations include instability in biological tissues and poor intracellular delivery, hindering their clinical application.
Purpose of the Study:
- To review cellular and intracellular delivery mechanisms for enhancing oligonucleotide (ON) activity.
- To investigate methods that improve ON cellular accumulation and endosomal escape.
- To address the future prospects of ON delivery systems in gene therapy.
Main Methods:
- Review of existing literature on oligonucleotide delivery systems.
- Analysis of cellular and intracellular mechanisms governing ON uptake and trafficking.
- Evaluation of chemical modifications and delivery vehicles for improved ON performance.
Main Results:
- Oligonucleotides are typically internalized via endocytosis and accumulate in endosomes, where their activity is often diminished.
- The efficiency of ONs moving from endosomes to the cytoplasm is critical for therapeutic effect.
- Various delivery strategies and chemical modifications show promise in overcoming these barriers.
Conclusions:
- Effective oligonucleotide therapy hinges on overcoming intracellular delivery hurdles, particularly endosomal escape.
- Developing advanced delivery systems is vital for increasing ON cellular uptake and therapeutic efficacy.
- Future research should focus on optimizing delivery methods to enhance endosome-to-cytoplasm transfer for improved gene therapy outcomes.