2. Academic Validation
  3. Hierarchically collapsible nanoactuator modulates mitochondrial ferroptosis-bioenergetic homeostasis cascade to decouple ischemic stroke

Hierarchically collapsible nanoactuator modulates mitochondrial ferroptosis-bioenergetic homeostasis cascade to decouple ischemic stroke

  • Cell Rep Med. 2026 Mar 17;7(3):102640. doi: 10.1016/j.xcrm.2026.102640.
Guangjie Sun 1,  Yize Dong 1,  Ying Wang 2,  Yihong Su 1,  Jiajun Chen 1,  Jiali Deng 1,  Lan Luo 1,  Xinyue Cao 2,  Weiping Lu 2,  Kai Chen 2,  Meihua Yu 3,  Yujie Xie 4,  Bingcang Huang 5,  Yu Chen 6
Affiliations

Affiliations

  • 1 Department of Radiology, Gongli Hospital of Shanghai Pudong New Area, Shanghai 200135, China; School of Gongli Hospital Medical Technology, University of Shanghai for Science and Technology, Shanghai 200093, China.
  • 2 Department of Radiology, Gongli Hospital of Shanghai Pudong New Area, Shanghai 200135, China.
  • 3 Materdicine Lab, School of Life Sciences, Shanghai University, Shanghai 200444, China. Electronic address: [email protected].
  • 4 School of Medicine, Shanghai University, Shanghai 200444, China. Electronic address: [email protected].
  • 5 Department of Radiology, Gongli Hospital of Shanghai Pudong New Area, Shanghai 200135, China. Electronic address: [email protected].
  • 6 Materdicine Lab, School of Life Sciences, Shanghai University, Shanghai 200444, China; School of Medicine, Shanghai University, Shanghai 200444, China; Shanghai Institute of Materdicine, Shanghai 200052, China. Electronic address: [email protected].
PMID: 41742403 DOI: 10.1016/j.xcrm.2026.102640
Abstract

Ischemic stroke, a life-altering cerebrovascular emergency triggered by prolonged cerebral hypoperfusion, remains a therapeutic enigma. Current interventions struggle with ischemia-reperfusion injury; restoring blood flow unleashes Reactive Oxygen Species (ROS), driving secondary neuronal damage and functional loss. Ischemia-induced mitochondrial dysfunction heightens oxidative stress and hastens neuronal death. We address oxidative-stress-driven neuronal injury by engineering a hierarchically collapsible nanoactuator suppressing mitochondrial Ferroptosis and restoring cellular energy homeostasis. The nanoactuator integrates a diselenide-crosslinked shell conjugated with a mitochondrial-targeting peptide, enabling blood-brain barrier penetration and mitochondrial delivery. Its collapsible core, composed of an ATP-gadolinium coordination polymer encapsulating a Ferroptosis inhibitor, enables MRI-guided tracking and ROS-responsive drug release. In damaged mitochondria, the nanoactuator replenishes ATP, restores membrane potential, reduces ROS levels, and alleviates Ferroptosis. Intravenous administration in a transient middle cerebral artery occlusion (tMCAO) mouse model demonstrated robust multi-mechanistic neuroprotection. This hierarchical nanoactuator platform offers a strategy for ischemic stroke and related neurodegenerative diseases.

Keywords

energetic homeostasis; ferroptosis; ischemia-reperfusion injury; ischemic stroke; nanoactuator; oxidative stress.

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