Targeting engineered cell membrane camouflaged gallic acid-cerium nanozyme for intercepting the inflammation-free radical vicious cycle in atherosclerosis

Atherosclerotic plaques are characterized by oxidative stress and inflammatory responses, which amplify each other in a vicious cycle, leading to progressive plaque destabilization and ultimately serious cardiovascular events. Therefore, the development of nanoformulations with synergistically enhanced anti-inflammatory and antioxidant activities and effective aggregation in plaques is ideal. In this study, we prepared a gallic acid (GA)-cerium metal polyphenol nanoconjugate (GA-Ce, GC) through cerium ions-mediated oxidative coupling of GA, followed by functionalization of its surface with a phosphatidylserine (PS)-binding peptide (GC-PS, GCP), and subsequent encapsulation with a P-selectin glycoprotein ligand-1 (PSGL-1)-overexpressing endothelial cell membrane (PEM) to harvest a biomimetic PEM@GCP nanozyme. The in vitro results showed that PEM@GCP could effectively scavenge free radicals, promote macrophage differentiation to the M2 phenotype, reduce the content of proinflammatory cytokines, inhibit lipid peroxidation, and inhibit apoptosis with cytoprotective functions. In the atherosclerotic mouse model, compared with the control, PSGL-1-based PEM@GCP resulted in a 4.04-fold greater accumulation in plaque lesions. Through its synergistic anti-inflammatory and antioxidant activities, it effectively blocks the vicious cycle of inflammation-oxidative stress, thereby significantly ameliorating the pathological microenvironment and leading to a substantial 71.3% reduction in the plaque area. These studies elucidate the therapeutic potential of a biomimetic metal-polyphenol nanozyme in the treatment of atherosclerosis, demonstrating its potential as a promising candidate for clinical translation.