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

Abstract

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.

Cascade Catalytically Released Nitric Oxide‐Driven Nanomotor with Enhanced Penetration for Antibiofilm

“…Although much progress has been made in improving the antibiofilm ability of NO, its poor ability to penetrate biofilm remains a major challenge in the treatment of bacterial infections. [ 13,14 ]…”

“…Unlike passive nanodrugs, nanomotor is capable of converting different energies from the environment (chemical fuels, electricity, ultrasound, optics, and magnetic fields) into autonomous motion, [ 15–21 ] and has been used in drug delivery systems for the treatment of diseases. [ 19,22–14 ] Specifically, nanomotor can eradicate biofilm through the enhanced penetration effect and local delivery of antibacterial agents. For example, Escarpa et al.…”

Recent advances of natural and bioengineered extracellular vesicles and their application in vascular regeneration

“…In recent years, nanotechnology has been widely used in the diagnosis and treatment of cardiovascular diseases [ 63 , 64 ]. However, it is difficult for synthetic nano-drugs to target vascular injured sites through cell biological interactions.…”

A Chemotactic Colloidal Motor

“…Beyond the drug delivery, researchers have found drug‐free treatments that rely on chemotactic colloidal motors. In this method, the colloidal motors were modified with specific chemicals to simulate the “eat me” signal to macrophages when the colloidal motors chemotaxis to the lesion site, so that the diseased cells can be cleared by the immune system [24] . Although it has been made great progress in the chemotactic mechanism, there are also challenges and limitation for the chemotactic colloidal motors toward the biomedical applications.…”

“…In this method, the colloidal motors were modified with specific chemicals to simulate the "eat me" signal to macrophages when the colloidal motors chemotaxis to the lesion site, so that the diseased cells can be cleared by the immune system. [24] Although it has been made great progress in the chemotactic mechanism, there are also challenges and limitation for the chemotactic colloidal motors toward the biomedical applications. First, the chemotaxis has been verified in the individuals of colloidal motors, however, the chemotactic behaviors of the colloidal motor swarms is not clear yet.…”