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Polyethyleneimine-coated Iron Oxide Nanoparticles as a Vehicle for the Delivery of Small Interfering RNA to Macrophages In Vitro and In Vivo
Published on: February 5, 2019
Macrophage-Targeted Lipid Nanoparticle Delivery of microRNA-146a to Mitigate Hemorrhagic Shock-Induced Acute
Qinqin Fei1,2,3,4, Emily M Shalosky2,4, Ryelie Barnes2,4
1Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, 500 West 12th Avenue, Columbus, Ohio 43210, United States.
Abstract:
The pro-inflammatory response of alveolar macrophages to injurious physical forces during mechanical ventilation is regulated by the anti-inflammatory microRNA, miR-146a. Increasing miR-146a expression to supraphysiologic levels using untargeted lipid nanoparticles reduces ventilator-induced lung injury but requires a high initial dose of miR-146a making it less clinically applicable. In this study, we developed mannosylated lipid nanoparticles that can effectively mitigate lung injury at the initiation of mechanical ventilation with lower doses of miR-146a. We used a physiologically relevant humanized in vitro coculture system to evaluate the cell-specific targeting efficiency of the mannosylated lipid nanoparticle. We discovered that mannosylated lipid nanoparticles preferentially deliver miR-146a to alveolar macrophages and reduce force-induced inflammation in vitro. Our in vivo study using a clinically relevant mouse model of hemorrhagic shock-induced acute respiratory distress syndrome demonstrated that delivery of a low dose of miR-146a (0.1 nmol) using mannosylated lipid nanoparticles dramatically increases miR-146a levels in mouse alveolar macrophages and decreases lung inflammation. These data suggest that mannosylated lipid nanoparticles may have the therapeutic potential to mitigate lung injury during mechanical ventilation.
Insights
Mannose-coated nanoparticles deliver miR-146a to lung macrophages, reducing ventilator-induced lung injury with lower doses. This targeted approach offers a promising therapy for mitigating lung damage during mechanical ventilation.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Pulmonary Medicine
Background:
- Mechanical ventilation can cause lung injury due to pro-inflammatory responses in alveolar macrophages.
- The microRNA miR-146a is a key regulator of this inflammatory response.
- Current methods to increase miR-146a levels require high doses, limiting clinical applicability.
Purpose of the Study:
- To develop a targeted delivery system for miR-146a to reduce ventilator-induced lung injury.
- To evaluate the efficacy of mannosylated lipid nanoparticles for delivering miR-146a to alveolar macrophages.
Main Methods:
- Development of mannosylated lipid nanoparticles for miR-146a delivery.
- Evaluation of nanoparticle targeting efficiency in a humanized *in vitro* coculture system.
- Assessment of therapeutic efficacy in a mouse model of hemorrhagic shock-induced acute respiratory distress syndrome.
Main Results:
- Mannosylated lipid nanoparticles demonstrated preferential delivery of miR-146a to alveolar macrophages *in vitro*.
- These nanoparticles effectively reduced force-induced inflammation *in vitro*.
- A low dose of miR-146a delivered via mannosylated lipid nanoparticles significantly increased miR-146a levels and decreased lung inflammation *in vivo*.
Conclusions:
- Mannosylated lipid nanoparticles represent a promising strategy for targeted miR-146a delivery.
- This approach can mitigate lung injury during mechanical ventilation with reduced miR-146a dosage.
- Further research may lead to novel therapeutic interventions for ventilator-induced lung injury.
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