Addressing Hypoxia as a Barrier to mRNA Lipid Nanoparticle Medicines: Mechanisms, Materials, and Therapies

Hypoxia is a common hallmark of human disease that is characterized by insufficient oxygen available to cells, tissues, and organs 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. In this seminar, we present a three-pronged approach to addressing hypoxia as a barrier to mRNA lipid nanoparticle (LNP) medicine - mechanism, materials, and therapies. In mechanism, we demonstrate that hypoxia can decrease mRNA LNP efficacy by upwards of 80%, a potency reduction that correlates with decreased intracellular ATP levels (but not with impaired cellular uptake or endosomal escape) in hypoxic vs normoxic cells 1,2 In materials, we describe the development of chemistries that can restore mRNA LNP performance across a range of oxygenation conditions and nanoparticle formulations in vitro and in vivo.3,4,5 In therapies, we translate these mechanistic and materials insights to improve mRNA LNP therapy across a variety of disease states with a particular focus on developing gene therapies for non-small cell lung cancer treatments.6,7 Taken together, the goal of this seminar is to underscore strategies to overcome the deleterious impact of hypoxia on mRNA LNP therapies, while more broadly demonstrating the value of mechanism- and materials-driven workflows for advancing gene therapies in the study and prevention of disease.