Abstract
Peripheral vasculopathies cause severe wound hypoxia inducing the hypoxamiR miR-210. High level of miR-210, persisting in wound-edge tissue as ischemic memory, suppresses oxidative metabolism and inhibits cell proliferation necessary for healing. In wound-edge tissue of chronic wound patients, elevated miR-210 was tightly associated with inhibition of epidermal cell proliferation as evident by lowered Ki67 immunoreactivity. To inhibit miR-210 in murine ischemic wound-edge tissue, we report the formulation of antihypoxamiR functionalized gramicidin lipid nanoparticles (AFGLN). A single intradermal delivery of AFGLN encapsulating LNA-conjugated anti-hypoximiR-210 (AFGLN(miR-210)) lowered miR-210 level in the ischemic wound-edge tissue. In repTOP™mitoIRE mice, AFGLN(miR-210) rescued keratinocyte proliferation as visualized by in vivo imaging system (IVIS). (31)P NMR studies showed elevated ATP content at the ischemic wound-edge tissue following AFGLN(miR-210) treatment indicating recovering bioenergetics necessary for healing. Consistently, AFGLN(miR-210) improved ischemic wound closure. The nanoparticle based approach reported herein is effective for miR-directed wound therapeutics warranting further translational development.