4.8 Article

Carrier-Free Trehalose-Based Nanomotors Targeting Macrophages in Inflammatory Plaque for Treatment of Atherosclerosis

Journal

ACS NANO
Volume 16, Issue 3, Pages 3808-3820

Publisher

AMER CHEMICAL SOC
DOI: 10.1021/acsnano.1c08391

Keywords

atherosclerosis; trehalose; macrophage; nanomotor; autophagy; carrier-free

Funding

  1. National Natural Science Foundation of China [22175096, 81771952]
  2. Social Development Project of Jiangsu Natural Science Foundation [BE2019744]
  3. Jiangsu Collaborative Innovation Center of Biomedical Functional Materials
  4. Qinglan Project Foundation of Colleges and Universities of Jiangsu Province
  5. Priority Academic Program Development of Jiangsu Higher Education Institution

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The study reports a carrier-free nanomotor that utilizes nitric oxide (NO) as a driving force to induce autophagy of macrophages and improve abnormal lipid metabolism in atherosclerosis. The nanomotor achieves precise targeting and high biological availability with the use of trehalose, L-arginine, and phosphatidylserine.
Inducing autophagy of macrophages to improve abnormal lipid metabolism is an important way to treat atherosclerosis (AS). Yet, the current application of the mammalian target of rapamycin (mTOR)-dependent autophagy inducers is limited by the side effects and lack of targeting and low biological availability. Herein, a kind of nitric oxide (NO)-driven carrier-free nanomotor based on the reaction between trehalose (Tr, one of the mTOR-independent autophagy inducers), L-arginine (Arg), and phosphatidylserine (PS) is reported. The developed nanomotors use NO as the driving force, which is generated from the reaction between Arg and excessive reactive oxygen species (ROS) and inducible nitric oxide synthase (iNOS) specifically presenting in the AS microenvironment. The high expression of ROS and iNOS in the AS site can be used as chemoattractants to induce chemotaxis behavior of the nanomotors to achieve the first-step targeting an AS plaque. Subsequently, the eat me signal sent by PS is exploited to precisely target to the macrophages in the AS plaque, realizing the plaque-macrophage-targeted effect by this step-by-step strategy. In vitro and in vivo results confirm that the introduction of the concept of carrier-free nanomotors has greatly improved the biological availability of trehalose (the dose can be reduced from 2.5 g kg(-1) in previous reports to 0.01 g kg(-1) in this work). Particularly, consumed ROS and the production of NO during the targeting process also play positive roles, in which the former regulates the M2 polarization of macrophages and the latter promotes the reconstruction of an endothelial barrier, which contributes to the multilink treatment of AS.

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