Macrophage-Targeted Lipid Nanoparticle Delivery of microRNA-146a to Mitigate Hemorrhagic Shock-Induced Acute Respiratory Distress Syndrome

The pro-inflammatory response of alveolar macrophagesto injuriousphysical forces during mechanical ventilation is regulated by theanti-inflammatory microRNA, miR-146a. Increasing miR-146a expressionto supraphysiologic levels using untargeted lipid nanoparticles reducesventilator-induced lung injury but requires a high initial dose ofmiR-146a making it less clinically applicable. In this study, we developedmannosylated lipid nanoparticles that can effectively mitigate lunginjury at the initiation of mechanical ventilation with lower dosesof miR-146a. We used a physiologically relevant humanized in vitro coculture system to evaluate the cell-specifictargeting efficiency of the mannosylated lipid nanoparticle. We discoveredthat mannosylated lipid nanoparticles preferentially deliver miR-146ato alveolar macrophages and reduce force-induced inflammation in vitro. Our in vivo study using a clinicallyrelevant mouse model of hemorrhagic shock-induced acute respiratorydistress syndrome demonstrated that delivery of a low dose of miR-146a(0.1 nmol) using mannosylated lipid nanoparticles dramatically increasesmiR-146a levels in mouse alveolar macrophages and decreases lung inflammation.These data suggest that mannosylated lipid nanoparticles may havethe therapeutic potential to mitigate lung injury during mechanicalventilation.

Automated summary

Alveolar macrophages respond to injurious physical forces during mechanical ventilation by inducing inflammation, which 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, limiting its clinical applicability. This study developed mannosylated lipid nanoparticles that effectively mitigate lung injury at the initiation of mechanical ventilation with lower doses of miR-146a.