Sequential blood-brain barrier-penetrating and microglial-mitochondria-targeting nanosystem for ischemic stroke therapy
5 affiliations
- 1Department of Neurosurgery, Jiujiang City Key Laboratory of Cell Therapy/Human Genetic Resources Innovation Center, The First People's Hospital of Jiujiang City, Jiujiang, 332000, China
- 2Department of Cardiovascular Surgery, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, China
- 3Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, 430060, China
- 4Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, 430060, China
- 5College of Life Science and Health, Wuhan University of Science and Technology, Wuhan, 430065, China
Abstract
Ischemic stroke (IS) causes severe neurological deficits closely linked to microglial overactivation after ischemia/reperfusion (I/R) injury, a process governed by mitochondrial homeostasis. However, restoring microglial mitochondrial function across the blood–brain barrier (BBB) remains challenging. Here, we report a sequentially targeted nanosystem, M-BPM@TGPB, for I/R injury therapy. It comprises a triphenylphosphonium (TPP)-modified, gadolinium-doped Prussian blue core and a mannose-modified BV2–platelet hybrid membrane shell. This design integrates mannose for BBB penetration, platelet membrane for lesion targeting, BV2 membrane for microglial uptake, and TPP for mitochondrial localization, enabling precise vascular-to-subcellular delivery. In vitro, the nanosystem crossed the BBB, localized to BV2 mitochondria, scavenged reactive oxygen species (ROS), restored mitochondrial function, and inhibited inflammation. In a mouse model of middle cerebral artery occlusion/reperfusion (MCAO/R), the intravenously administered nanosystem accumulated in microglial mitochondria, scavenged mitochondrial ROS (mtROS), restored mitochondrial homeostasis, promoted M1-to-M2 polarization, suppressed neuroinflammation, reduced neuronal apoptosis, and promoted angiogenesis, thereby reducing infarct volume from 36.61% to 10.57% and the modified neurological severity score (mNSS) from 14 to 2.5. It also exhibited favorable biocompatibility and enhanced magnetic resonance imaging (MRI) contrast. Critically, rather than broadly scavenging ROS, this strategy specifically restores microglial mitochondrial function, shifting the therapeutic focus from general antioxidant approaches to organelle-specific intervention. This work may offer a promising design paradigm for nanotherapies targeting central nervous system disorders in which mitochondrial dysfunction and neuroinflammation are core pathological drivers.
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BibTeX
@article{chen2026sequential,
title = {{Sequential blood-brain barrier-penetrating and microglial-mitochondria-targeting nanosystem for ischemic stroke therapy}},
author = {Qing Chen and Jin Wang and Hui Shu and Xiaoxing Xiong and Lijuan Gu and Jian Tian and Youjia Tang},
journal = {Materials Today Bio},
year = {2026},
month = oct,
doi = {10.1016/j.mtbio.2026.103786},
url = {https://doi.org/10.1016/j.mtbio.2026.103786},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - Sequential blood-brain barrier-penetrating and microglial-mitochondria-targeting nanosystem for ischemic stroke therapy
AU - Qing Chen
AU - Jin Wang
AU - Hui Shu
AU - Xiaoxing Xiong
AU - Lijuan Gu
AU - Jian Tian
AU - Youjia Tang
PY - 2026
DA - 2026/10/27
JO - Materials Today Bio
DO - 10.1016/j.mtbio.2026.103786
UR - https://doi.org/10.1016/j.mtbio.2026.103786
AB - Ischemic stroke (IS) causes severe neurological deficits closely linked to microglial overactivation after ischemia/reperfusion (I/R) injury, a process governed by mitochondrial homeostasis. However, restoring microglial mitochondrial function across the blood–brain barrier (BBB) remains challenging. Here, we report a sequentially targeted nanosystem, M-BPM@TGPB, for I/R injury therapy. It comprises a triphenylphosphonium (TPP)-modified, gadolinium-doped Prussian blue core and a mannose-modified BV2–platelet hybrid membrane shell. This design integrates mannose for BBB penetration, platelet membrane for lesion targeting, BV2 membrane for microglial uptake, and TPP for mitochondrial localization, enabling precise vascular-to-subcellular delivery. In vitro, the nanosystem crossed the BBB, localized to BV2 mitochondria, scavenged reactive oxygen species (ROS), restored mitochondrial function, and inhibited inflammation. In a mouse model of middle cerebral artery occlusion/reperfusion (MCAO/R), the intravenously administered nanosystem accumulated in microglial mitochondria, scavenged mitochondrial ROS (mtROS), restored mitochondrial homeostasis, promoted M1-to-M2 polarization, suppressed neuroinflammation, reduced neuronal apoptosis, and promoted angiogenesis, thereby reducing infarct volume from 36.61% to 10.57% and the modified neurological severity score (mNSS) from 14 to 2.5. It also exhibited favorable biocompatibility and enhanced magnetic resonance imaging (MRI) contrast. Critically, rather than broadly scavenging ROS, this strategy specifically restores microglial mitochondrial function, shifting the therapeutic focus from general antioxidant approaches to organelle-specific intervention. This work may offer a promising design paradigm for nanotherapies targeting central nervous system disorders in which mitochondrial dysfunction and neuroinflammation are core pathological drivers.
SN - 2590-0064
ER -