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AntihypoxamiR functionalized gramicidin lipid nanoparticles rescue against ischemic memory improving cutaneous wound
Subhadip Ghatak1, Jilong Li2, Yuk C Chan1
1Center for Regenerative Medicine & Cell-Based Therapies, Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
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 (AFGLNmiR-210) lowered miR-210 level in the ischemic wound-edge tissue. In repTOP™mitoIRE mice, AFGLNmiR-210 rescued keratinocyte proliferation as visualized by in vivo imaging system (IVIS). 31P NMR studies showed elevated ATP content at the ischemic wound-edge tissue following AFGLNmiR-210 treatment indicating recovering bioenergetics necessary for healing. Consistently, AFGLNmiR-210 improved ischemic wound closure. The nanoparticle based approach reported herein is effective for miR-directed wound therapeutics warranting further translational development.
Insights
New nanoparticles effectively target miR-210, a microRNA that hinders wound healing by suppressing cell proliferation. This approach restores cellular energy and promotes healing in ischemic wounds.
Area of Science:
- Biomedical Engineering
- Molecular Biology
- Wound Healing Research
Background:
- Peripheral vasculopathies lead to wound hypoxia, inducing miR-210, a microRNA that suppresses oxidative metabolism and cell proliferation, impairing wound healing.
- Elevated miR-210 levels in chronic wound patients' tissue correlate with inhibited epidermal cell proliferation, evidenced by reduced Ki67.
- Ischemic memory, characterized by persistent high miR-210, poses a significant challenge in treating chronic wounds.
Purpose of the Study:
- To develop and evaluate a novel nanoparticle-based therapeutic strategy to inhibit miR-210 in ischemic wound-edge tissue.
- To assess the efficacy of antihypoxamiR functionalized gramicidin lipid nanoparticles (AFGLN) in restoring keratinocyte proliferation and improving bioenergetics.
- To investigate the potential of miR-210 inhibition for promoting ischemic wound closure.
Main Methods:
- Formulation of antihypoxamiR functionalized gramicidin lipid nanoparticles (AFGLN) encapsulating LNA-conjugated anti-miR-210.
- Single intradermal delivery of AFGLNmiR-210 into murine ischemic wound-edge tissue.
- Assessment of miR-210 levels, keratinocyte proliferation (using repTOP™mitoIRE mice and IVIS), ATP content (via 31P NMR), and wound closure.
Main Results:
- AFGLNmiR-210 successfully lowered miR-210 levels in the ischemic wound-edge tissue.
- Keratinocyte proliferation was rescued in repTOP™mitoIRE mice treated with AFGLNmiR-210.
- Treatment led to elevated ATP content, indicating restored bioenergetics, and improved ischemic wound closure.
Conclusions:
- Nanoparticle-mediated inhibition of miR-210 is a viable strategy for treating ischemic wounds.
- The developed AFGLN platform demonstrates potential for miR-directed wound therapeutics.
- This approach warrants further translational development for clinical application in wound healing.
