Inflammation resolution-based treatment of atherosclerosis using biomimetic nanocarriers loaded with specialized pro-resolving lipid mediators

Recent studies have shown that chronic inflammation in atherosclerotic (ATH) lesions is due to an inability to resolve the inflammatory response. We evaluated the therapeutic potential of specialized pro-resolving mediators (SPMs) incorporated into biomimetic lipid nanoemulsions covered with macrophage membranes (Bio-LN/SPMs) to enhance their stability, targeting, and bioactivity in resolving atherosclerotic plaque inflammation. We utilized both <i>in vitro</i> and <i>in vivo</i> experimental models to test this hypothesis. <i>In vitro,</i> we found that Bio-LN/SPMs significantly reduced the inflammatory markers VCAM-1, MCP-1 in TNF-α-activated endothelial and smooth muscle cells, and iNOS, and NLRP3 in LPS-activated macrophages. In contrast, free SPMs exhibited a more modest effect. <i>In vivo</i>, the i.v. administration of Bio-LN/SPMs in ApoE-deficient mice with progressive atherosclerotic lesions developed after administration for 4 and 8 weeks of a high-fat diet, reduced plasma triglycerides, improved renal function, and decreased plasma proteins associated with complement activation and inflammation (i.e. C4d, C5b-9, IL-6, and MCP-1) to a greater extent than other treatment groups. Bio-LN/SPMs also affected circulated monocyte subpopulations by increasing the percentage of anti-inflammatory Ly6C^low monocytes and reducing that of pro-inflammatory Ly6C^high monocytes. Additionally, they promoted the transition of macrophages in atherosclerotic plaques to a reparative M2 phenotype. They decreased the production of TNF-α, IL-1β, and IL-6 cytokines, along with lipid deposits in the aorta of ApoE-deficient mice. These findings demonstrate the improved therapeutic efficacy of Bio-LN/SPMs compared to unincorporated SPMs and standard nanoemulsions (LN/SPMs), emphasizing their potential as a novel approach for treating atherosclerosis and other inflammatory diseases.