The Problem:
Antisense oligonucleotides (ASOs), designed to regulate specific genes, face two major delivery challenges: endosomal entrapment and inefficient nuclear localization. Only a small fraction of ASOs escape from endosomes to reach the cytosol and nucleus, limiting their ability to effectively modulate gene expression.
The Potential Solution:
Optimizing ASO delivery is crucial for enhancing therapeutic efficacy. Researchers aim to develop innovative methods that both facilitate endosomal escape and promote nuclear localization, overcoming the primary delivery challenges.
The Methods:
- Endosomal Escape Agents: Utilizing pH-sensitive materials and small molecules like cationic lipids to disrupt endosomal membranes.
- Peptide and Non-Viral Conjugates: Using bacterial toxin-derived or viral peptides to enhance membrane penetration and escape.
- Direct Cytosolic Delivery: Modifying lipid nanoparticles (LNPs) and employing arginine-rich peptides to bypass endosomes entirely.
- Nuclear Localization Signals (NLS): Incorporating cationic peptide sequences to transport ASOs through the nuclear pore complex efficiently.
Main Findings:
Research suggests that combining multiple delivery strategies, such as non-toxic endosomal escape mechanisms with NLS-enhanced delivery systems, could significantly improve ASO localization and therapeutic effectiveness. Ongoing exploration in this area may revolutionize ASO-based treatments, enabling them to target challenging gene-related diseases more efficiently.
