Atom‐Efficient Cerium‐Based Molecular Cages as Biocompatible Reactive Oxygen Scavengers

The development of reactive oxygen species (ROS)‐scavenging materials for biomedical applications has been constrained by the difficulty associated with achieving simultaneously broad‐spectrum scavenging efficiency and acceptable biosafety. To date, ceria/nanoceria systems have been explored for this purpose; however, they suffer from limited cerium‐atom utilization. Inspired by the atom‐economy concept of single‐atom catalysis, we report a cerium‐based molecular‐cage strategy for treating oxidative stress‐driven atherosclerosis (AS). It involves mixed‐valent cerium ions (Ce 3+ /Ce 4+ ) that are stably confined within tailored molecular cages and that mimic the cooperation between oxygen vacancies and cerium redox cycling in CeO 2 . This endows the four representative cages of this study with an ability to scavenge superoxide anion (O 2 • − ), hydrogen peroxide (H 2 O 2 ), and hydroxyl radical (•OH). Their catalytic function can be readily modulated through the ROS‐responsive release of the molecular cages at local lesion sites. This capability was found to alleviate oxidative stress and associated inflammation, as inferred from the finding that a lead cerium cage incorporated into a biocompatible nanoparticle reduces the progression of AS in a mouse model. A reduction in plaque lipid deposition, macrophage accumulation, necrotic core formation, and MMP‐9‐associated matrix was seen.