Minocycline‐Loaded Cerium Oxide Nanoparticles for the Enhanced Treatment of Intracerebral Hemorrhage

Abstract Inflammatory responses and neuronal ferroptosis, which are associated with abnormal accumulation of reactive oxygen species (ROS), exert crucial damaging effects on the brain after intracerebral hemorrhage (ICH). In this study, minocycline (MC)‐loaded cerium oxide nanoparticles (CeO 2 ‐MC) are constructed for combined ICH treatment. Ultra‐small CeO 2 (≈5 nm) synthesized via a high‐temperature approach exhibits powerful free‐radical scavenging and iron‐chelating abilities. In vitro experiments demonstrated that CeO 2 ‐MC effectively attenuated the ROS levels in mouse microglial cells and neurons following oxyhemoglobin stimulation. In addition, CeO 2 ‐MC exhibits iron chelation properties and stabilizes the mitochondrial membrane potential, thereby promoting anti‐inflammatory responses and preventing neuronal ferroptosis. In an intracerebral hemorrhage (ICH) mouse model, CeO 2 ‐MC exhibited robust free radical scavenging capabilities and demonstrated the ability to preserve mitochondrial morphology and function, mitigate brain edema, and maintain blood–brain barrier integrity by inhibiting neuroinflammation and ferroptosis. Neurobehavioral tests demonstrated that CeO 2 ‐MC significantly ameliorated spatial learning ability and sensorimotor function after ICH. Consequently, a general strategy using CeO 2 nanoparticles to augment the therapeutic efficacy of MC highlights a new perspective for the in‐depth treatment of ICH.