EBioMedicine. 2021 Dec 05;74:103725. doi: 10.1016/j.ebiom.2021.103725. Epub 2021 Dec 05.
Phospholipid nanoparticles: Therapeutic potentials against atherosclerosis via reducing cholesterol crystals and inhibiting inflammation.
EBioMedicine
Yonghong Luo, Yanhong Guo, Huilun Wang, Minzhi Yu, Kristen Hong, Dan Li, Ruiting Li, Bo Wen, Die Hu, Lin Chang, Jifeng Zhang, Bo Yang, Duxin Sun, Anna S Schwendeman, Y Eugene Chen
Affiliations
Affiliations
- Department of Internal Medicine, Cardiovascular Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Second Xiangya Hospital, Central South University, Hunan Province, China.
- Department of Internal Medicine, Cardiovascular Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA. Electronic address: [email protected].
- Department of Internal Medicine, Cardiovascular Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA.
- Second Xiangya Hospital, Central South University, Hunan Province, China.
- Department of Cardiac Surgery, University of Michigan Medical School, Ann Arbor, MI, USA.
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA; Biointerfaces Institute, University of Michigan, Ann Arbor, MI, USA. Electronic address: [email protected].
- Department of Internal Medicine, Cardiovascular Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Cardiac Surgery, University of Michigan Medical School, Ann Arbor, MI, USA. Electronic address: [email protected].
PMID: 34879325
DOI: 10.1016/j.ebiom.2021.103725
Abstract
BACKGROUND: Atherosclerosis-related cardiovascular diseases (CVDs) are the leading cause of mortality worldwide. Cholesterol crystals (CCs) induce inflammation in atherosclerosis and are associated with unstable plaques and poor prognosis, but no drug can remove CCs in the clinic currently.
METHODS: We generated a phospholipid-based and high-density lipoprotein (HDL)-like nanoparticle, miNano, and determined CC-dissolving capacity, cholesterol efflux property, and anti-inflammation effects of miNano in vitro. Both normal C57BL/6J and Apoe-deficient mice were used to explore the accumulation of miNano in atherosclerotic plaques. The efficacy and safety of miNano administration to treat atherosclerosis were evaluated in the Ldlr-deficient atherosclerosis model. The CC-dissolving capacity of miNano was also detected using human atherosclerotic plaques ex vivo.
FINDINGS: We found that miNano bound to and dissolved CCs efficiently in vitro, and miNano accumulated in atherosclerotic plaques, co-localized with CCs and macrophages in vivo. Administration of miNano inhibited atherosclerosis and improved plaque stability by reducing CCs and macrophages in Ldlr-deficient mice with favorable safety profiles. In macrophages, miNano prevented foam cell formation by enhancing cholesterol efflux and suppressed inflammatory responses via inhibiting TLR4-NF-κB pathway. Finally, in an ex vivo experiment, miNano effectively dissolved CCs in human aortic atherosclerotic plaques.
INTERPRETATION: Together, our work finds that phospholipid-based and HDL-like nanoparticle, miNano, has the potential to treat atherosclerosis by targeting CCs and stabilizing plaques.
FUNDING: This work was supported by the National Institutes of Health HL134569, HL109916, HL136231, and HL137214 to Y.E.C, HL138139 to J.Z., R21NS111191 to A.S., by the American Heart Association 15SDG24470155, Grant Awards (U068144 from Bio-interfaces and G024404 from M-BRISC) at the University of Michigan to Y.G., by the American Heart Association 19PRE34400017 and Rackham Helen Wu award to M.Y., NIH T32 GM07767 to K. H., Barbour Fellowship to D.L.
Copyright © 2021. Published by Elsevier B.V.
Keywords: Atherosclerosis; Cholesterol crystal; HDL; Inflammation; Nanoparticle
Conflict of interest statement
Declaration of Competing Interest The authors have declared that no conflict of interest exists.
Publication Types
