Journal
ACTA BIOMATERIALIA
Volume 155, Issue -, Pages 304-322Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.actbio.2022.10.059
Keywords
miR; miR31; miR132; Nanoparticles; Electrospinning; Polymer patch; Nucleic acid delivery; Peptide; RALA; Wound healing
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The downregulation of miR-31 and miR-132 is linked to delayed wound healing. In this study, it was hypothesized that delivering miR-31 and miR-132 intracellularly, either individually or in a blend, could enhance tissue repair. The use of a blend formulation can minimize toxicity and maximize therapeutic effects.
Downregulation of microRNA-31 (miR-31) and microRNA-132 (miR-132) has been associated with delayed wound healing. Therefore, it was hypothesised that intracellular delivery of miR-31 and miR-132, both as individual and blend formulations, could promote tissue repair. The use of a blend could minimise poten-tial toxicity and achieve synergistic effects, thus maximising the therapeutic effect. miR-31 and miR-132 were condensed with a 30-mer positively charged amphipathic peptide, RALA, to form nanocomplexes with an average size < 200 nm and zeta-potential >10 designed to facilitate cellular internalisation. This enabled a fold increase in miR-31 and miR-132 expression of >10 0,0 0 0 in a murine fibroblast cell line (NCTC-929) and a skin human keratinocyte cell line (HaCaT), with intracellular delivery > 70% for indi-vidual and blend formulations. Moreover, incubation with the nanocomplexes increased the migration of HaCaT cells >25% at 4 and 8 h post-incubation, as well as downregulation of EMP-1 and RASA1 and HB-EGF and RASA1, target genes for miR-31 and miR-132, respectively. Electrospinning was then employed to produce an alginate/polyvinyl alcohol/ciprofloxacin nanofibrous wound patch to facilitate the controlled delivery of the nanocomplexes. Nanofibres were crosslinked with glutaraldehyde to improve stability in aqueous solvents, and they were proven to be biocompatible with antimicrobial activity without cellu-lar attachment to avoid injury upon removal. RALA/miR nanoparticles were incorporated to the nanofi-brous wound dressing and in vivo wound healing studies using C57BL/6J mice demonstrated a > 60% acceleration in the wound closure rate at Day 7 post-wounding, a >1.5 increase in epidermal thickness, and a >2 increase in blood vessel count with respect to commercial and untreated controls. Taken to-gether, this data proves that delivery of RALA/miR-31 and RALA/miR-132 from an alginate/polyvinyl al-cohol/ciprofloxacin nanofibrous wound dressing constitutes an advanced therapy for wound healing, by accelerating wound closure and improving healed tissue quality.
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