Shear force and cholesterol affinity responsive drug delivery system for treating inflammation and abnormal lipid metabolism in atherosclerosis

Abstract

Inflammatory infiltration and lipid metabolism disorder are two main characteristics of atherosclerosis (AS) plaque microenvironment. They interact to form a malignant positive feedback cycle, which aggravates the development of AS disease. Therefore, simultaneous improvement of inflammation and lipid metabolism will provide a significant therapeutic effect on AS. To achieve this goal, we first prepared FCD (Fuc-TK-CD) by grafting β-cyclodextrin (β-CD) to fucoidan (Fuc) via reactive oxygen species (ROS)-responsive sulfhydryl disulfide bond (TK), then loaded resveratrol (Res) through the host-guest interaction. Finally, we coated it on the surface of SeNPs through SeO bonds to obtain FCD-Se/Res nanoplatforms. FCD-Se/Res can actively recognize P-selectin and penetrate the AS plaque interior. Subsequently, FCD-Se/Res responded to the high shear force and abundant cholesterol in the plaque microenvironment to release Res, reducing AS plaque inflammation by reversing M1 macrophages to M2 phenotype. Meanwhile, TK bonds broke in response to high ROS levels in the plaque, making β-CD free to clear excessive pathogenic cholesterol from plaques. Benefiting from the integrated multifunctionality, FCD-Se/Res can break the vicious cycle between inflammation and disrupted lipid metabolism, jointly stabilize vulnerable plaques, and exert efficient anti-AS effects. The pharmacodynamic results revealed a significantly reduced plaque vulnerability index (VI) from 4.07 to 0.40 after FCD-Se/Res treatment.