Programmed prodrug breaking the feedback regulation of P-selectin in plaque inflammation for atherosclerotic therapy

Inflammation is the main driver of the aggravation of arteriosclerosis, and the complex inflammatory response in plaque is usually the result of the interaction of various cells and cytokines. Therefore, it is difficult to comprehensively regulate the inflammatory process of arteriosclerosis by intervening a single target, resulting in the poor effect of existing treatment method. Based on our clinical findings that P-selectin stably and highly expressed in patients' plaque endothelial cells, the programmed prodrug, low molecular weight heparin-indomethacin nanoparticles (LI NPs), were established as anti-inflammatory agent to multiphase inhibit arteriosclerosis by cascade interference of P-selectin. Structurally, LI NPs was obtained by simple esterification of low molecular weight heparin and indomethacin without any additives, guaranteeing the biocompatibility and applicability of LI NPs. Functionally, LI NPs could interfere with P-selectin in the inflammatory process, such as inhibiting macrophage adhesion, reducing the secretion of inflammatory factors, and inducing macrophage apoptosis. In the arteriosclerosis mice model, LI NPs significantly reduced the plaque area and showed satisfactory curative effect, which is related to the intervention of the multiphase inflammation between endothelial cells and macrophages. In conclusion, the programmed prodrug LI NPs offered a promising approach for the clinical therapy of arteriosclerosis.