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

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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