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
  • 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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