Title

Dynamically Enhancing Plaque Targeting Via a Positive Feedback Loop using Multifunctional Biomimetic Nanoparticles for Plaque Regression

Abstract

A paradigm shift from preventive therapy to aggressive plaque regression and eventual eradication is much needed to address increasing atherosclerotic burden and risks. Herein, we report a biologically inspired dual-targeting multifunctional recombinant high-density lipoprotein (rHDL)-mimicking core-shell nanoplatform. It is composed of an ATP-responsive ternary polyplexes core for SR-A siRNA and catalase complexation, and a phosphatidylserine-modified rHDL-based outer shell for SR-BI and CD36 targeting, in which pitavastatin is packaged. We demonstrated that dual-targeting biomimetic core-shell nanoparticles dynamically enhanced macrophage CD36 targeting in the plaques by establishing a positive feedback loop via the reciprocal regulation of SR-A and CD36. Positive feedback-enabled accumulation of the nanoparticles in the atherosclerotic plaques increased by 3.3-fold following 4-week repeated administration. A 3-month dosage regimen of the dual-targeting rHDL-mimicking nanoparticles reduced plaque areas by 65.8%, and decreased macrophages by 57.3%. Collectively, this work shows that dynamically enhancing plaque targeting via a positive feedback loop and dual action of cholesterol deposition inhibition and efflux enhancement accomplished with our novel multifunctional biomimetic nanoparticles provides a new way to regress plaques and alleviate the atherosclerotic burden.

Department(s)

Chemical and Biochemical Engineering

Research Center/Lab(s)

Center for Research in Energy and Environment (CREE)

Comments

This work was supported by National Major Science and Technology Project of China (grant no. 2017YFA0205400 ) and National Natural Science Foundation of China (grant no. 81773669 ). The research was supported by Graduate Cultivation Innovative Project of Jiangsu Province (grant no. KYCX17_0677 ) and a Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions.

Keywords and Phrases

Atherosclerosis; Dual-targeting; Nanocarrier; Plaque regression; Plaque targeting; Positive feedback loop

International Standard Serial Number (ISSN)

0168-3659; 1873-4995

Document Type

Article - Journal

Document Version

Citation

File Type

text

Language(s)

English

Rights

© 2019 Elsevier B.V., All rights reserved.

Publication Date

28 Aug 2019

PubMed ID

31295543

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