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Journal article
Physicochemical Targeting of Lipid Nanoparticles to the Lungs Induces Clotting: Mechanisms and Solutions
Advanced materials (Weinheim), pe2312026
23 Feb 2024
PMID: 38394670
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
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 we examined lung tropic LNPs, whose organ tropism derives from containing either a cationic or ionizable lipid conferring a positive zeta potential. Surprisingly, we found these LNPs induce massive thrombosis. We show such thrombosis in the lungs and other organs, and 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, we engineered multiple solutions that enable positively charged LNPs to target the lungs while ameliorating thrombosis. Our findings implicate thrombosis as a major barrier that blood erects against LNPs with positive zeta potential and illustrate how physicochemical targeting approaches must be investigated early for risks and re-engineered with a careful understanding of biological mechanisms. This article is protected by copyright. All rights reserved.
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Details
- Title
- Physicochemical Targeting of Lipid Nanoparticles to the Lungs Induces Clotting: Mechanisms and Solutions
- Creators
- Serena Omo-Lamai - University of PennsylvaniaMarco E Zamora - Drexel UniversityManthan N Patel - University of PennsylvaniaJichuan Wu - University of PennsylvaniaJia Nong - University of PennsylvaniaZhicheng Wang - University of PennsylvaniaAlina Peshkova - University of PennsylvaniaAparajeeta Majumder - University of PennsylvaniaJilian R Melamed - University of PennsylvaniaLiam S Chase - University of PennsylvaniaEno-Obong Essien - University of PennsylvaniaDrew Weissman - University of PennsylvaniaVladimir R Muzykantov - University of PennsylvaniaOscar A Marcos-Contreras - University of PennsylvaniaJacob W Myerson - University of PennsylvaniaJacob S Brenner - University of Pennsylvania
- Publication Details
- Advanced materials (Weinheim), pe2312026
- Publisher
- American Physical Society (APS)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- School of Biomedical Engineering, Science, and Health Systems
- Web of Science ID
- WOS:001183884600001
- Scopus ID
- 2-s2.0-85187506637
- Other Identifier
- 991021855577304721
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InCites Highlights
Data related to this publication, from InCites Benchmarking & Analytics tool:
- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Chemistry, Multidisciplinary
- Chemistry, Physical
- Materials Science, Multidisciplinary
- Nanoscience & Nanotechnology
- Physics, Applied
- Physics, Condensed Matter