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Enhanced localized pressure-mediated non-viral gene delivery
James E Dixon1,2, Vanessa Wellington3, Alaa Elnima3
1Regenerative Medicine & Cellular Therapies Division, School of Pharmacy, The University of Nottingham Biodiscovery Institute (BDI), University of Nottingham, Nottingham, NG7 2RD, UK. james.dixon@nottingham.ac.uk.
Drug Delivery and Translational Research
|March 12, 2025
Summary
Applying pressure significantly enhances the delivery of gene therapies like Glycosaminoglycan (GAG)-binding enhanced transduction (GET) nanoparticles into tissues. This breakthrough improves drug distribution for treating large tissue areas in regenerative medicine.
Area of Science:
- Biomedical Engineering
- Drug Delivery
- Regenerative Medicine
Background:
- Effective topical drug delivery requires efficient tissue penetration, a challenge for macromolecule therapeutics like peptides and nucleic acids.
- Targeting large, complex tissue volumes (e.g., wounds, infections) is hindered by poor drug diffusion.
- Glycosaminoglycan (GAG)-binding enhanced transduction (GET) nanoparticles offer intracellular delivery but face diffusion limitations.
Purpose of the Study:
- To investigate methods for enhancing the tissue penetration and distribution of GET nanoparticles.
- To evaluate the impact of pressure-driven fluid flow on gene delivery efficiency in milli/centimetre scales.
- To demonstrate the potential of pressure application for localized gene transfer in accessible tissues.
Main Methods:
- Utilized GET nanoparticles with GAG-binding peptides and cell-penetrating peptides (CPPs).
- Tested nanoparticle diffusion in collagen scaffolds to assess intrinsic penetration capabilities.
- Adapted clinical negative pressure wound therapy (NPWT) and positive pressure (PP) systems to apply pressure differentials.
- Evaluated localized gene transfer in vitro using cell scaffolds and ex vivo using skin explants.
Main Results:
- Simple GET formulations showed limited diffusion into tissue matrix.
- Pressure application, via NPWT and PP systems, significantly enhanced nanoparticle distribution and effective gene delivery.
- Demonstrated localized gene transfer in vitro and enhanced transfection of ex vivo skin.
- Confirmed that pressure differentials drive fluid flow, improving delivery over milli/centimetre scales.
Conclusions:
- Pressure-driven fluid flow is a transformative method for enhancing the intra-tissue localization and delivery of nanomedicines and gene therapeutics.
- This approach overcomes diffusion limitations, enabling effective gene delivery to large tissue volumes.
- The controlled application of pressure offers a novel strategy for regenerative medicine and treating accessible tissues.
