ABSTRACT
Stereochemistry can alter small-molecule pharmacokinetics, safety and efficacy. However, it is unclear whether the stereochemistry of a single compound within a multicomponent colloid such as a lipid nanoparticle (LNP) can influence its activity in vivo. Here we report that LNPs containing stereopure 20α-hydroxycholesterol (20α) delivered mRNA to liver cells up to 3-fold more potently than LNPs containing a mixture of both 20α- and 20ß-hydroxycholesterols (20mix). This effect was not driven by LNP physiochemical traits. Instead, in vivo single-cell RNA sequencing and imaging revealed that 20mix LNPs were sorted into phagocytic pathways more than 20α LNPs, resulting in key differences between LNP biodistribution and subsequent LNP functional delivery. These data are consistent with the fact that nanoparticle biodistribution is necessary, but not sufficient, for mRNA delivery, and that stereochemistry-dependent interactions between LNPs and target cells can improve mRNA delivery.
Subject(s)
Lipids , Nanoparticles , Lipids/chemistry , RNA, Messenger/genetics , Tissue Distribution , Nanoparticles/chemistryABSTRACT
One of the crucial steps in image mosaicing is global alignment, which requires finding the best image registration parameters by employing nonlinear minimization methods over correspondences between overlapping image pairs for a dataset. Based on graph theory, we propose a simple but efficient method to reduce the number of overlapping image pairs without any noticeable effect on the final mosaic quality. This reduction significantly lowers the computational cost of the image mosaicing process. The proposed method can be applied in a topology estimation process to reduce the number of image matching attempts. The method has been validated through experiments on challenging underwater image sequences obtained during sea trials with different unmanned underwater vehicles.
