美国佐治亚理工学院James E. Dahlman研究团队取得一项新突破。他们发现纳米颗粒立体化学依赖的内吞途径可改善mRNA的体内递送。2023年3月2日出版的《自然—化学》杂志发表了这项成果。

在该研究中，团队报道了含有光学纯的20α-羟基胆固醇（20α）的脂质纳米颗粒（LNP）向肝细胞递送mRNA的能力比含有20α-和20β-羟基胆固醇混合物（20mix）的LNP高3倍。这一效应与LNP的理化特性无关。相反，体内单细胞RNA测序和成像显示，20mix LNP比20α LNP更多地被分类到胞噬途径，导致LNP生物分布和之后LNP功能性递送之间的关键差异。这些数据与“纳米颗粒的生物分布对于mRNA的递送是必要不充分条件的事实”相符，也与“LNP-靶细胞之间立体化学依赖的相互作用可以改善mRNA递送”的观察一致。

据了解，立体化学可以改变小分子的药代动力学、安全性和有效性。然而，之前尚不清楚多组分胶体（如脂质纳米颗粒）中单个化合物的立体化学是否会影响其在体内的活性。

附：英文原文

Title: Nanoparticle stereochemistry-dependent endocytic processing improves in vivo mRNA delivery

Author: Hatit, Marine Z. C., Dobrowolski, Curtis N., Lokugamage, Melissa P., Loughrey, David, Ni, Huanzhen, Zurla, Chiara, Da Silva Sanchez, Alejandro J., Radmand, Afsane, Huayamares, Sebastian G., Zenhausern, Ryan, Paunovska, Kalina, Peck, Hannah E., Kim, Jinwhan, Sato, Manaka, Feldman, Jacob I., Rivera, Michael-Alexander, Cristian, Ana, Kim, YongTae, Santangelo, Philip J., Dahlman, James E.

Issue&Volume: 2023-03-02

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 20β-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.

DOI: 10.1038/s41557-023-01138-9

Source: https://www.nature.com/articles/s41557-023-01138-9