Facilitating plasmid nuclear delivery by interfering with the selective nuclear pore barrier

Area of Science:

• Cell Biology
• Biophysics
• Drug Delivery

Background:

• Nuclear pore complexes (NPCs) regulate nucleocytoplasmic transport, acting as a barrier with a diffusion cutoff of 40 kDa.
• Efficient nuclear delivery of large therapeutic nanoparticles (e.g., 150 kDa pDNA) is crucial for gene and chemotherapy but is limited by NPC size restrictions.

Purpose of the Study:

• To identify compounds that can increase the NPC transport cutoff, enabling nuclear delivery of large therapeutic molecules.
• To evaluate the efficacy and mechanism of identified compounds in facilitating pDNA delivery into human vascular endothelial cells.

Main Methods:

• Screening of various compounds for their ability to enhance nuclear transport of pDNA.
• Assessing the impact of the lead compound on NPC structure and function.
• Evaluating cell viability following compound treatment.

Main Results:

• 1,6-hexanediol (1,6-HD) was identified as a compound that facilitates pDNA nuclear delivery in 10-20% of treated human vascular endothelial cells.
• 1,6-HD functions by transiently disrupting interactions between nucleoporins (Nups) within the NPC channel.
• The compound demonstrated good cell viability, even at high concentrations.

Conclusions:

• 1,6-hexanediol shows promise as a strategy to overcome NPC transport limitations for large nanoparticles.
• This finding opens avenues for developing new therapeutic approaches for enhanced nuclear delivery of gene and chemotherapy agents.