Bioinspired Ruthenium Arene Complex with Pseudo-Vacant Coordination Sites as Efficient Small-Molecular Antioxidant...

With the ongoing progress in coronary interventional therapy, the progression of atherosclerosis is no longer solely governed by its natural course. Postprocedural neointimal hyperplasia and plaque formation markedly increase the risk of cardiovascular events, where chronic, unresolved inflammation and the overproduction of reactive oxygen species (ROS) play a critical role in driving plaque development. Drawing inspiration from the reaction mechanisms of intracellular antioxidant defense systems, we report the de novo design of a ruthenium arene complex (RuC₆H₆) with pseudo-vacant coordination sites, which serves as efficient small-molecular antioxidant enzyme mimics for biocatalytic ROS elimination and the attenuation of vascular restenosis. Our findings reveal that the ligands in RuC₆H₆ undergo rapid hydrolysis during the reaction and chloride ligands are replaced by H₂O₂, thereby generating abundant reactive sites and conferring the complex with efficient, broad-spectrum, and stable ROS-scavenging properties. When encapsulated in liposomes (Lipid-Ru), the complex effectively reprogrammed macrophages from the M1 phenotype, diminished the secretion of inflammatory cytokines, and suppressed foam cell formation. Moreover, the Lipid-Ru administration led to a significant reduction in smooth muscle cell migration and neointimal area, ultimately alleviating vascular restenosis. This class of structurally tunable arene ruthenium complexes thus provides a promising strategy for designing biomimetic antioxidant reagents, holding considerable potential for the treatment of diverse inflammation-associated diseases.