Polyplex-Loaded Hydrogels for Local Gene Delivery to Human Dermal Fibroblasts

Abstract

Impaired cutaneous healing, leading to chronic wounds, affects between 2 and 6% of the total population in most developed countries and it places a substantial burden on healthcare budgets. Current treatments involving antibiotic dressings and mechanical debridement are often not effective, causing severe pain, emotional distress and social isolation in patients for years or even decades, ultimately resulting in limb amputation. Alternatively, gene therapy (such as mRNA therapies) emerges as a viable option to promote wound healing through modulation of gene expression. However, protecting the genetic cargo from degradation and efficient transfection into primary cells remain significant challenges in the push to clinical translation. Another limiting aspect of current therapies is the lack of sustained release of drugs to match the therapeutic window. Herein, we have developed an injectable, biodegradable and biocompatible hydrogel-based wound dressing that delivers pBAE nanoparticles in a sustained manner over a range of therapeutic windows. We also demonstrate that pBAE nanoparticles, successfully used in previous <i>in vivo</i> studies, protect the mRNA load and efficiently transfect human dermal fibroblasts upon sustained release from the hydrogel wound dressing. This prototype wound dressing technology can enable the development of novel gene therapies for the treatment of chronic wounds.

Polymer-based non-viral vectors for gene therapy in the skin

“…Duran-Mota et al 121 developed a viscoelastic injectable PBAE/PEG hydrogel with embedded PBAE polyplexes to enable the efficient transfection of human dermal fibroblasts. Injection prompted the formation of in situ hydrogels that adapted to irregular and deep wounds, such as those observed in chronic ulcers.…”

Editorial: Special Issue on Advanced Biomedical Hydrogels

“…For example, Oliva, Borros, and coworkers report a hydrogel-based wound healing patch containing mRNA-encapsulated nanoparticles. 29 The hydrogel protected the genetic cargo from degradation and improved transfection. Additionally, Anseth and colleagues developed negatively charged nanogels as an inexpensive protective reservoir for protein therapeutics with high isoelectric point via electrostatic interactions.…”