Hierarchically Collapsible Nanoactuator Sequentially Modulates Mitochondrial Ferroptosis-Bioenergetic Homeostasis Cascade to Decouple Ischemic Stroke Pathogenesis

In this work, we address oxidative stress-driven neuronal injury by engineering a hierarchically collapsible nanoactuator capable of sequentially suppressing mitochondrial ferroptosis and restoring cellular energy homeostasis. The nanoactuator integrates a soft diselenide-crosslinked shell conjugated with a mitochondrial-targeting peptide, enabling efficient blood-brain barrier penetration and precise mitochondrial delivery. Its collapsible core, composed of an ATP-gadolinium coordination polymer encapsulating a ferroptosis inhibitor, allows for MRI-guided tracking and ROS-responsive drug release. Upon cellular uptake, the nanoactuator rapidly replenishes ATP in damaged mitochondria, restores mitochondrial membrane potential, reduces ROS levels, and effectively alleviates oxidative and ferroptotic damage. Intravenous administration in a transient middle cerebral artery occlusion (tMCAO) mouse model demonstrated robust multi-mechanistic neuroprotective efficacy. This hierarchical nanoactuator platform offers a robust and adaptable strategy for modulating regulated cell death pathways and enhancing therapeutic outcomes in ischemic stroke and related neurodegenerative diseases