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Remodeling of the lesional macrophages in atherosclerotic plaques from pro-inflammatory M1 to pro-resolving M2 phenotype is emerging as a promising approach to atherosclerosis treatment. Tilianin (Til), as a natural plant-derived ingredient, has the potential to suppress atherosclerosis progression. However, the poorly aqueous solubility and capacity of targeted plaques limit to clinic transformation of Til. Furthermore, whether Til can remodel the lesional macrophage phenotype remains uninvestigated. Herein, we developed a lesional macrophage-targeted Til lipid nanoparticles (FA@Til-LNPs) via folate modification and investigated their therapeutic efficiency and potential mechanisms for atherosclerosis treatment. We observed that the FA@Til-LNPs not only improved solubility and bioavailability, but also actively targeted M1 macrophages in atherosclerotic plaques, and the internalized FA@Til-LNPs could effectively regulate macrophage polarization toward the M2 phenotype. The nanotherapeutics reduced plaque areas and substantially improved plaque stability by effectively reducing necrotic core area and augmenting the collagen cap area in high-fat diet-fed ApoE−/− mice. Mechanistically, RNA-sequencing analysis revealed that the FA@Til-LNPs inhibited the pro-inflammatory signaling pathway by down-regulating the expression of pro-inflammatory genes associated with cytokine and chemokine pathways in lesional macrophages. This study first developed the innovative targeting nanotherapeutics of Til to regulate macrophage phenotype for atherosclerosis treatment.
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