Journal
ACS NANO
Volume -, Issue -, Pages -Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsnano.3c01814
Keywords
Mannosylated lipid nanoparticle; acute respiratory distresssyndrome; inflammation; microRNA; alveolarmacrophages
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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.
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.
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