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Updated: Sep 21, 2026
Microfluidics-Assisted Selective Depolarization of Axonal Mitochondria
Published on: August 4, 2022
Stepwise neutrophil-to-neuron targeting nanotherapy for mitochondrial protection and blood-brain barrier preservation
Xurui Gu1, Sai Wang2, Lei Chen2
1Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; National Clinical Research Center for Geriatric Disease (Xiangya Hospital), Central South University, Changsha, Hunan 410008, China; Multi-Modal Monitoring Technology for Severe Cerebrovascular Disease of Human Engineering Research Center, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Brain Health Center of Hunan Province, Human Brain Disease Biological Resources Platform of Hunan Province, Changsha, Hunan 410008, China; Human Brain Disease Biological Resources Platform of Hunan Province, Changsha, China; FuRong Laboratory, Changsha 410078, Hunan, China; Hunan Provincial Key Laboratory of Neurocritical Care Medicine, China; Hunan Provincial Quality Management Center for Brain Injury Assessment, China; Department of Pharmacy, Xiangya Hospital, Central South University, No. 87, Xiangya Road, Changsha 410008, Hunan Province, China.
Abstract:
Ischemic stroke is a leading cause of mortality and long-term disability worldwide, yet the clinical efficacy of reperfusion therapies remains severely constrained by a narrow therapeutic time window and secondary ischemia-reperfusion injury. Preserving the viability of the ischemic penumbra through early, multi-target neuroprotection represents a promising strategy to extend this window; however, effective approaches that simultaneously address neuronal mitochondrial dysfunction and blood-brain barrier (BBB) disruption are lacking. Here, we report a dual-modal, stepwise-targeting lipid nanoparticle (DM-LNP) platform that integrates mitochondrial protection with matrix metalloproteinase-12 (MMP-12) silencing to achieve coordinated neurovascular protection in ischemic stroke. DM-LNP is engineered with a sialic acid-based neutrophil-targeting outer layer and a reactive oxygen species (ROS)-responsive thioketal linker that enables ligand switching to expose a neuron-targeting Tet1 peptide within the ischemic microenvironment. This design allows sequential neutrophil-mediated BBB traversal (Modal I) and precise neuronal targeting (Modal II). Functionally, DM-LNP delivers MMP-12 siRNA to suppress downstream MMP activation and preserve BBB integrity, while a spermidine-derived gene carrier promotes Pink1-Parkin-mediated mitophagy, restores mitochondrial homeostasis, reduces oxidative stress, inhibits neuronal apoptosis, and drives microglial polarization toward an anti-inflammatory phenotype. In transient and prolonged middle cerebral artery occlusion models, DM-LNP significantly improves cerebral blood flow recovery, reduces infarct volume, alleviates neurological deficits, and extends the effective reperfusion window up to 8 h post-ischemia. Together, this work establishes a multifunctional, ROS-responsive nanotherapeutic strategy that stabilizes the neuron-microglia-BBB axis and offers a viable approach for extending reperfusion benefits in ischemic stroke.
