Physicochemical Targeting of Lipid Nanoparticles to the Lungs Induces Clotting Mechanisms and Solutions

Physicochemical Targeting of Lipid Nanoparticles to the Lungs Induces Clotting : Mechanisms and Solutions

© 2024 The Authors. Advanced Materials published by Wiley‐VCH GmbH.

Détails bibliographiques
Publié dans:Advanced materials (Deerfield Beach, Fla.). - 1998. - 36(2024), 26 vom: 13. Juni, Seite e2312026
Auteur principal: Omo-Lamai, Serena (Auteur)
Autres auteurs: Zamora, Marco E, Patel, Manthan N, Wu, Jichuan, Nong, Jia, Wang, Zhicheng, Peshkova, Alina, Majumder, Aparajeeta, Melamed, Jilian R, Chase, Liam S, Essien, Eno-Obong, Weissman, Drew, Muzykantov, Vladimir R, Marcos-Contreras, Oscar A, Myerson, Jacob W, Brenner, Jacob S
Format: Article en ligne
Langue:English
Publié: 2024
Accès à la collection:Advanced materials (Deerfield Beach, Fla.)
Sujets:Journal Article drug delivery lipid nanoparticles nanomedicine side effects thrombosis Lipids Thrombin EC 3.4.21.5 Fibrinogen 9001-32-5
Description
Résumé:© 2024 The Authors. Advanced Materials published by Wiley‐VCH GmbH.
Lipid nanoparticles (LNPs) have become the dominant drug delivery technology in industry, holding the promise to deliver RNA to up or down-regulate any protein of interest. LNPs have mostly been targeted to specific cell types or organs by physicochemical targeting in which LNP's lipid compositions are adjusted to find mixtures with the desired tropism. Here lung-tropic LNPs are examined, whose organ tropism derives from containing either a cationic or ionizable lipid conferring a positive zeta potential. Surprisingly, these LNPs are found to induce massive thrombosis. Such thrombosis is shown in the lungs and other organs, and it is shown that it is greatly exacerbated by pre-existing inflammation. This clotting is induced by a variety of formulations with cationic lipids, including LNPs and non-LNP nanoparticles, and even by lung-tropic ionizable lipids that do not have a permanent cationic charge. The mechanism depends on the LNPs binding to and then changing the conformation of fibrinogen, which then activates platelets and thrombin. Based on these mechanisms, multiple solutions are engineered that enable positively charged LNPs to target the lungs while ameliorating thrombosis. The findings illustrate how physicochemical targeting approaches must be investigated early for risks and re-engineered with a careful understanding of biological mechanisms
Description:Date Completed 26.06.2024
Date Revised 29.06.2024
published: Print-Electronic
UpdateOf: bioRxiv. 2023 Jul 25:2023.07.21.550080. doi: 10.1101/2023.07.21.550080. - PMID 37546837
Citation Status MEDLINE
ISSN:1521-4095
DOI:10.1002/adma.202312026