Enhanced localized pressure-mediated non-viral gene delivery

Dixon, James E.; Wellington, Vanessa; Elnima, Alaa; Savers, Amelie; Blokpoel Ferreras, Lia A.; Jalal, Aveen R.; Eltaher, Hoda M.

Abstract

Topically applied therapies must not only be effective at the molecular level but also efficiently access the target site which can be on milli/centimetre-scales. This bottleneck is particularly inhibitory for peptide and nucleic acid macromolecule drug delivery strategies, especially when aiming to target wounded, infected, and poorly perfused tissues of significant volume and geometry. Methods to drive fluid-flow or to enhance physical distribution of such formulations after local administration in accessible tissues (skin, eye, intestine) would be transformative in realizing the potential of such therapeutics. We previously developed a technology termed Glycosaminoglycan (GAG)-binding enhanced transduction (GET) to efficiently deliver a variety of cargoes intracellularly, using GAG-binding peptides and cell penetrating peptides (CPPs) in the form of nanoparticles. Herein, we demonstrate that the most simplistic GET formulation is relatively poor in diffusing into tissue matrix (tested in collagen scaffolds). Changing nanoparticle physicochemical properties can enhance penetration, however the use of a pressure differential, generating fluid-flow significantly enhances effective gene delivery over milli/centimetre scales. We adapted clinically used pressure systems to administer both negative (Negative pressure (NP) wound therapy; NPWT) and positive pressures (PP; Insufflator). Pressure differences generated enhanced distribution, and we were able to show for the first-time localized gene transfer in vitro in cell scaffolds and enhanced transfection of ex vivo skin explants. The ability to simply control intra-tissue localization of gene delivery on milli/centimetre scales using pressure application will facilitate new drug delivery strategies for accessible tissues. Importantly site-specific enhancement of penetration and activity of novel nanotechnologies and gene therapeutics could be transformative for future regenerative medicine strategies.

Citation

Dixon, J. E., Wellington, V., Elnima, A., Savers, A., Blokpoel Ferreras, L. A., Jalal, A. R., & Eltaher, H. M. (2025). Enhanced localized pressure-mediated non-viral gene delivery. Drug Delivery and Translational Research, https://doi.org/10.1007/s13346-025-01827-7

• Journal Article Type: Article
• Acceptance Date: Feb 24, 2025
• Online Publication Date: Mar 12, 2025
• Publication Date: Mar 12, 2025
• Deposit Date: Mar 4, 2025
• Publicly Available Date: Mar 13, 2026
• Journal: Drug Delivery and Translational Research
• Print ISSN: 2190-393X
• Electronic ISSN: 2190-3948
• Publisher: Springer Verlag
• Peer Reviewed: Peer Reviewed
• DOI: https://doi.org/10.1007/s13346-025-01827-7
• Keywords: GAG-binding enhanced transduction (GET); Negative pressure wound 18 therapy; gene transfer; transfection; Skin 19
• Public URL: https://nottingham-repository.worktribe.com/output/46187361
• Publisher URL: https://link.springer.com/article/10.1007/s13346-025-01827-7
• Additional Information: Accepted: 24 February 2025; First Online: 12 March 2025; : ; : Not applicable.; : All authors consent to publication.; : All authors declare no competing interests.