Understanding Hypoxia's Impact on mRNA Lipid Nanoparticle Therapies

Hypoxia is a common hallmark of human disease that is characterized by abnormally low oxygen levels in the body. While the effects of hypoxia on many small molecule-based drugs are known, its effects on several classes of next-generation medications including messenger RNA therapies warrant further study. Here, we provide an efficacy and mechanism driven study that details how hypoxia impacts the cellular response to messenger RNA Lipid Nanoparticle therapies. In brief, our work provides a comparative analysis as to how various states of oxygenation impact lipid nanoparticle-delivered mRNA expression, cellular association, endosomal escape, and intracellular ATP concentrations following treatment with 4 different lipid nanoparticle chemistries, 3 different cell lines, 4 different oxygenation ratios, and 6 different reoxygenation conditions. In brief, our results demonstrate that hypoxia decreases the efficacy of mRNA Lipid Nanoparticles by upwards of 80%. Further, our results also suggest that these efficacy decreases correlate with decreased intracellular ATP levels in hypoxic cells. Taken collectively, our results suggest that cellular and tissue oxygen levels may be an important factor to consider when developing messenger RNA Lipid Nanoparticle based therapies.