Oral targeting tilianin nanoplatform mitigates atherosclerosis through promoting macrophage phagocytosis and anti-inflammation

Modulating macrophage function is an effective strategy for treating atherosclerosis. Our previous research shows that tilianin (Til) effectively regulates macrophage polarization. This immune modulation positions Til as a promising plant-derived therapeutic agent with potential for atherosclerosis treatment and management. Due to its biopharmaceutics classification system (BCS) IV drug properties, it is a challenge to delivering Til to macrophages in atherosclerotic plaques, especially via the oral route. Herein, we introduced a folate-modified oral Til nanocrystal liposome (FA-Lipo@Til NCs) that showed enhanced mucus permeability and transmembrane transport ability across the intestinal epithelium. It could subsequently target and accumulate in macrophages within aortic plaques. After three months of oral treatment with FA-Lipo@Til NCs in apolipoprotein E deficient (<i>ApoE</i> ^<i>-/-</i> ) mice with atherosclerosis, significant therapeutic effects were observed. The treatment effectively stabilized atherosclerotic plaques. Additionally, FA-Lipo@Til NCs effectively inhibited reactive oxygen species (ROS) production in macrophages, thereby reducing oxidative stress. The treatment also promoted macrophage polarization towards the anti-inflammatory M2 phenotype, enhancing their ability to clear apoptotic cells (efferocytosis) and resolving local inflammation. Notably, throughout the treatment period, significant alterations in blood lipid levels were observed. In summary, FA-Lipo@Til NCs offer a targeted and effective approach to regulate macrophage polarization while also hindering the advancement of atherosclerosis. Besides, our study proposes a promising therapeutic approach for atherosclerosis by leveraging an innovative oral targeted delivery system for BCS IV drugs.