Lipid nanoparticles (LNPs) are the leading nonviral technologies for the delivery of exogenous RNA to target cells in vivo. As systemic delivery platforms, these technologies are exemplified by Onpattro, an approved LNP‐based RNA interference therapy, administered intravenously and targeted to parenchymal liver cells. The discovery of systemically administered LNP technologies capable of preferential RNA delivery beyond hepatocytes has, however, proven more challenging. Here, preceded by comprehensive mechanistic understanding of in vivo nanoparticle biodistribution and bodily clearance, an LNP‐based messenger RNA (mRNA) delivery platform is rationally designed to preferentially target the hepatic reticuloendothelial system (RES). Evaluated in embryonic zebrafish, validated in mice, and directly compared to LNP–mRNA systems based on the lipid composition of Onpattro, RES‐targeted LNPs significantly enhance mRNA expression both globally within the liver and specifically within hepatic RES cell types. Hepatic RES targeting requires just a single lipid change within the formulation of Onpattro to switch LNP surface charge from neutral to anionic. This technology not only provides new opportunities to treat liver‐specific and systemic diseases in which RES cell types play a key role but, more importantly, exemplifies that rational design of advanced RNA therapies must be preceded by a robust understanding of the dominant nano–biointeractions involved.

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Approaches to locally deliver drugs to specific regions of the body are being developed for many clinical applications, including treating hemorrhage. Increasing the concentration of therapeutic coagulants in areas where clots are forming and growing can be achieved by applying them directly to the injury, such as with catheters or external delivery devices, or by systemically administering therapeutics that target molecular signals of vascular damage. Treating severe hemorrhage by external measures is challenging because blood flow pushes hemostatic agents outward, reducing their efficacy. This review explains that self-propelling particles may be used for delivering therapeutics, such as coagulation factors, small molecules, or other chemical or biological agents, deep into wounds during hemorrhage. A recent example of self-propelling particles is highlighted, where propulsion enhanced the efficacy of a formulation of thrombin and tranexamic acid in treating bleeding in two murine models of hemorrhage and a porcine model of fatal, non-compressible hemorrhage. Many agents exist which modulate clotting, and novel approaches that facilitate their safe delivery to sites of vascular injury could reduce the enormous number of deaths from hemorrhage that occur globally.