Turning Hot into Cold: Immune Microenvironment Reshaping for Atherosclerosis Attenuation Based on pH-Responsive shSiglec-1 Delivery System

Abstract

Current atherosclerosis treatment is based on a combination of cholesterol-lowering medication and low-fat diets; however, the clinical effect is unsatisfactory. It has been shown that the level of immune cell infiltration and pro-inflammatory factors in the atherosclerotic immune microenvironment (AIM) play important roles in the development and progression of atherosclerosis. Therefore, we hypothesized that reshaping “hot AIM” into “cold AIM” could attenuate atherosclerosis. For this purpose, we designed a pH-responsive and charge-reversible nanosystem, referred to as Au-PEI/shSiglec-1/PEI-acetylsalicylic acid (ASPA NPs) to effectively deliver shSiglec-1, which blocked the interactions between macrophages with CD8+ T/NKT cells, thus inhibiting immune cell infiltration. Further, we demonstrated that acetylsalicylic acid (ASA), detached from the pH-responsive PEI-ASA polymer, and inhibited lipid accumulation in macrophage, thereby decreasing the lipid antigen presentation. Additionally, reduced macrophage-produced inflammatory factors by ASA and low CD8+ T/NKT cell infiltration levels synergistically inhibit Th17 cell differentiation, thus further dramatically attenuating inflammation in AIM by decreasing the IL-17A production. Eventually, ASPA NPs efficiently reshaped AIM by inhibiting immune cell infiltration, lipid antigen presentation, and pro-inflammation, which provided a feasible therapeutic strategy for atherosclerosis immunotherapy.

Reduction of Reactive Oxygen Species Accumulation Using Gadolinium-Doped Ceria for the Alleviation of Atherosclerosis

“…5−8 Therefore, we performed the immunofluorescence staining of CD68 (a macrophage marker) on the aortic root sections (Figure 5j,k). 26 These results revealed a large number of macrophages in the atherosclerotic plaques of the untreated ApoE −/− model mice, while this number decreased in the Gd/ CeO 2 −5.0 treatment group. To further validate that Gd/ CeO 2 −5.0 reduced the overexpression of inflammatory factors within the arterial plaque sites, the levels of typical inflammatory factors (IL-1, IL-6, IL-17, and TNF-α) associated with the development of atherosclerosis in the arterial plaque were analyzed by ELISA.…”

“…As shown in Figure h,i, the Gd/CeO 2 –5.0 treatment significantly increased the collagen content to 53.6%, further demonstrating the remarkable antiatherosclerosis efficacy of Gd/CeO 2 –5.0. Moreover, the massive macrophage accumulation and low collagen content in plaque lesions reduced the plaque stability, thereby exacerbating atherosclerosis. − Therefore, we performed the immunofluorescence staining of CD68 (a macrophage marker) on the aortic root sections (Figure j,k) . These results revealed a large number of macrophages in the atherosclerotic plaques of the untreated ApoE –/– model mice, while this number decreased in the Gd/CeO 2 –5.0 treatment group.…”

“…The differentiation of macrophages into lipid-rich foam cells is a characteristic feature of early atherosclerosis. − An effective strategy to inhibit the formation of such foam cells is to reduce the lipid uptake and accumulation. To evaluate the effect of Gd/CeO 2 –5.0 on the formation of the foam cell, an ox-LDL-induced macrophage-derived foam cell model (RAW264.7) was established. , The preliminary observation was recorded by oil red O (ORO) staining. As shown in Figure a, the control cells demonstrated only a few red lipid droplets after ORO staining.…”

“…To evaluate the effect of Gd/CeO 2 −5.0 on the formation of the foam cell, an ox-LDL-induced macrophagederived foam cell model (RAW264.7) was established. 26,64 The preliminary observation was recorded by oil red O (ORO) staining. As shown in Figure 3a, the control cells demonstrated only a few red lipid droplets after ORO staining.…”

“…In addition, under inflammatory conditions, the oxidative stress generated by polymorphonuclear neutrophils, such as macrophages, forms interendothelial junctions, which accelerate the migration of inflammatory cells across the endothelial barrier, causing adverse effects in patients with atherosclerosis. − Therefore, reducing ROS levels in the lesion sites is crucial for atherosclerosis treatment. Recently, nanomedicine has been rapidly developed and extensively studied in the treatment of atherosclerosis due to its good biocompatibility as well as therapeutic effects. − Since ROS play an important role in the development of atherosclerosis, nanoceria with biomimetic characteristics of various enzymes (catalase, superoxide oxidase, etc.) can effectively scavenge intracellular and intraorganic ROS and have great potential in the treatment of atherosclerosis. − Therefore, increasing the antioxidant activity of the nanoceria becomes the key to achieving the highly efficient atherosclerosis treatment.…”