Activatable MRI‐Trackable Spherical Nucleic Acids for Idebenone Delivery Against Cerebral Ischemia–Reperfusion Injury

ABSTRACT Cerebral ischemia–reperfusion injury (IRI) is a key driver of poor prognosis in ischemic stroke. Idebenone (IDBN) shows promise for mitigating IRI, but its efficacy is limited by poor brain accumulation. Moreover, IDBN cannot be visually tracked, making it difficult to confirm whether it reaches the ischemic brain and exerts therapeutic effects. Here, IDBN functionalized with a reactive oxygen species (ROS)‐cleavable bond is grafted onto phosphorothioate‐modified DNA strands and co‐assembled with ultrasmall superparamagnetic iron oxide (USPIO) to form USPIO‐IDBN‐SNAs, where SNAs stands for spherical nucleic acids. Exploiting upregulated class A scavenger receptors, USPIO‐IDBN‐SNAs target the ischemic area without targeting modifications and increase local IDBN concentration. Hydrophobic IDBN inside the SNAs limits water access to USPIO clusters, suppressing their contrast‐enhancing ability. Under oxidative stress, IDBN is rapidly released and exerts remarkable protection. This release allows USPIO clusters to re‐establish contact with water, activating their contrast‐enhancing ability on T 2 ‐weighted imaging. Collectively, USPIO‐IDBN‐SNAs provide significant neuroprotection against IRI and offer a magnetic resonance imaging (MRI)‐visible platform to monitor IDBN release in the ischemic brain, presenting a promising theranostic approach for precise, trackable stroke therapy.