Carrier-Free Trehalose-Based Nanomotors Targeting Macrophages in Inflammatory Plaque for Treatment of Atherosclerosis
Carrier-Free Trehalose-Based Nanomotors Targeting Macrophages in Inflammatory Plaque for Treatment of Atherosclerosis
复制标题
基于无载体海藻糖的纳米马达靶向炎症斑块中的巨噬细胞治疗动脉粥样硬化
DOI：
10.1021/acsnano.1c08391
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发表时间：
2022
期刊：
影响因子：
17.1
通讯作者：
Mao C
中科院分区：
文献类型：
--
作者：
Wu Z;Zhou M;Tang X;Zeng J;Li Y;Sun Y;Huang J;Chen L;Wan M;Mao C
诱导巨噬细胞自噬以改善脂质代谢异常是治疗动脉粥样硬化（AS）的重要途径。然而，目前哺乳动物雷帕霉素靶向（mTOR）依赖性自噬诱导剂的应用受到副作用、缺乏靶向性和低生物利用度的限制。本文报道了一种一氧化氮（NO）驱动的无载体自噬纳米马达，该纳米马达是基于海藻糖（Tr，一种mTOR非依赖性自噬诱导剂）、L-精氨酸（Arg）和磷脂酰丝氨酸（PS）之间的反应而构建的.所开发的纳米电机使用NO作为驱动力，该驱动力是由Arg与AS微环境中特异性存在的过量活性氧簇（ROS）和诱导型一氧化氮合酶（iNOS）之间的反应产生的。ROS和iNOS在AS位点的高表达可用作化学引诱物以诱导纳米马达的趋化行为，从而实现第一步靶向AS斑块。随后，利用PS发出的“吃我”信号精确靶向AS斑块中的巨噬细胞，体外和体内实验结果证实，无载体纳米马达概念的引入大大提高了海藻糖的生物利用度（剂量可从以前报告的2.5 g kg-1降至本工作的0.01 g kg-1）。尤其是靶向过程中消耗的ROS和NO的产生也发挥了积极作用，前者调节巨噬细胞的M2极化，后者促进内皮屏障的重建，有助于AS的多环节治疗。
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 vitroandin vivoresults 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–1in previous reports to 0.01 g kg–1in 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.