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Adding a cationic helper lipid to a lipid nanoparticle (LNP) can increase lung delivery and decrease liver delivery. However, it remains unclear whether charge-dependent tropism is universal or, alternatively, whether it depends on the component that is charged. Here, we report evidence that cationic cholesterol-dependent tropism can differ from cationic helper lipid-dependent tropism. By testing how 196 LNPs delivered mRNA to 22 cell types, we found that charged cholesterols led to a different lung:liver delivery ratio than charged helper lipids. We also found that combining cationic cholesterol with a cationic helper lipid led to mRNA delivery in the heart as well as several lung cell types, including stem cell-like populations. These data highlight the utility of exploring charge-dependent LNP tropism.

 

On 30 June 2013, 19 Granite Mountain Hotshots firefighters were killed fighting a wildfire near Yarnell in the mountains of Central Arizona. They succumbed when the wildfire, driven by erratic winds, blocked their escape route and overran their location. A previous study is extended to simulate and analyze the downscale organization of convective circulations that redirected the wildfire, which started from the scale of the Rossby Wave Breaking over North America to a convective gust front that redirected the wildfire, trapping the firefighters. Five stages are found: Stage I, the initial deep prolonged gust front; Stage II, a front-to-rear jet and its ascending motions that organized high-based convection; Stage III, high-based dry microburst-induced downdrafts organized initially by ascending flow in Stage II that transported mass and entropy to the surface; Stage IV; multiple meso-γ-scale high centers and confluence zones formed that encompassed the firefighters’ location, which established a favorable environment leading to Stage V, canyon-scale circulations formed surrounding the fire. The atmosphere thus transitioned from supporting a deep and long-lived convective density current to elevated dry microbursts with mass and wind outflow into a canyon, redirecting the ongoing wildfire.