Phospholipid nanoparticles: Therapeutic potentials against atherosclerosis via reducing cholesterol crystals and inhibiting inflammation

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

EBioMedicine (Dec 2021)

Phospholipid nanoparticles: Therapeutic potentials against atherosclerosis via reducing cholesterol crystals and inhibiting inflammation

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

Yonghong Luo: 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
Yanhong Guo: Department of Internal Medicine, Cardiovascular Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Corresponding author at: Yanhong Guo, M.D., Ph.D., Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Huilun Wang: Department of Internal Medicine, Cardiovascular Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA
Minzhi Yu: Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
Kristen Hong: Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
Dan Li: Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
Ruiting Li: Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
Bo Wen: Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
Die Hu: Second Xiangya Hospital, Central South University, Hunan Province, China
Lin Chang: Department of Internal Medicine, Cardiovascular Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA
Jifeng Zhang: Department of Internal Medicine, Cardiovascular Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA
Bo Yang: Department of Cardiac Surgery, University of Michigan Medical School, Ann Arbor, MI, USA
Duxin Sun: Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
Anna S. Schwendeman: Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA; Biointerfaces Institute, University of Michigan, Ann Arbor, MI, USA; Corresponding author at: Anna S Schwendeman, Ph.D., Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA.
Y. Eugene Chen: 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; Corresponding author at: Y. Eugene Chen, M.D., Ph.D., Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA.

Journal volume & issue: Vol. 74
p. 103725

Abstract

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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.

Published in EBioMedicine

ISSN: 2352-3964 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Medicine (General)
Website: http://www.journals.elsevier.com/ebiomedicine/

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