ROS-responsive bionanodrug for atherosclerosis therapy via regulating glycolipid metabolism and cell crosstalk.

Atherosclerosis (AS) is a long-term inflammatory disorder marked by dysfunctional glycolipid metabolism, abnormal inflammatory response and intercellular crosstalk. Rosuvastatin (RSV), a first-line drug with lipid-lowering activity, fails to adequately modulate the inflammatory microenvironment of atherosclerotic plaques. The natural active ingredient shikonin (SKN) compensates for this limitation through inhibiting glycolysis and anti-inflammation. However, how to efficiently co-delivery them to the plaques remains challenging. In this study, we engineered a ROS-responsive nanosystem (TK-MLP@SR NPs) containing SKN and RSV. This system enables drug release in the plaque microenvironment with high ROS levels, prolongs circulation time, and achieves active lesion targeting. In vitro assay indicated the function of TK-MLP@SR NPs for inhibiting glycolysis and promoting fatty acid oxidation (FAO) in homocysteine-treated macrophages, thereby inhibiting foam cell formation and alleviating inflammation. Moreover, this nanosystem inhibited phenotype switch of vascular smooth muscle cell by restoring normal macrophage - smooth muscle cell crosstalk. In ApoE-/- mice, the accumulation of TK-MLP@SR NPs in the plaque reduced macrophage infiltration, thereby modulating the inflammatory microenvironment to restore smooth muscle cell function and improve the plaque stability, characterized by less lipid deposition, and increased collagen, along with smaller necrotic cores. Compared with free drugs, this strategy exhibited superior efficacy in regulating the plaque microenvironment by inhibiting lipid deposition. In summary, this work introduces a novel plaque environment-activated prodrug platform, providing valuable insights for clinical translation of AS therapy.