Cerebral endothelial cell-derived exosomes target injury sites to rescue cerebral energy crisis after traumatic brain injury

Traumatic brain injury (TBI) triggers a severe cerebral energy crisis causing irreversible neurodegeneration, with no effective targeted therapies available. Traditional TBI research neglects the secretory function of cerebral endothelial cells (CECs), and this study explored whether CEC-derived exosomes (CEC-Exos) exert SDF-1α/CXCR4-mediated lesion homing and rescue TBI-induced energy dysfunction, as well as the underlying mechanism. CECs endogenously express CXCR4, and TBI upregulates SDF-1α in the injured microenvironment; CEC-Exos inherit this SDF-1α/CXCR4-mediated homing property, which is attenuated by siCXCR4 knockdown.

Multi-omics identified miR-16-5p as the key exosomal effector that orchestrates cerebral metabolic rewiring, redirecting glucose metabolism from glycolysis to mitochondrial oxidative phosphorylation, reversing the TBI-induced energy crisis and restoring ATP production. In murine TBI models, CEC-Exos alleviated cerebral glucose hypometabolism, reduced lesion volume and neuronal apoptosis, and improved neurological recovery with these effects abolished by miR-16-5p depletion. Collectively, CEC-Exos serve as endogenous targeted therapeutic agents for TBI via SDF-1α/CXCR4-mediated homing and miR-16-5p-dependent metabolic regulation.

We also propose a novel neurovascular coupling mechanism where CEC-Exos act as “endogenous neuro-metabolic couplers” to improve neuronal energy metabolism, offering a new TBI treatment strategy. We thank the institutional core facility for experimental assistance and all laboratory members for their constructive input. This work was supported by the following grants: Joint Traditional Chinese Medicine (TCM) Science and Technology Program of National Demonstration Zones for Comprehensive TCM Reform (Grant No.

GZY-KJS-SD-2024-021); National Natural Science Foundation of China (Grant No. 82272253); Shandong Provincial Natural Science Foundation (Grant No. Department of Pharmacy, Zhongshan City People’s Hospital, Zhongshan, China School of Pharmaceutical Sciences, Zunyi Medical University, Zunyi, China Translational Pharmaceutical Laboratory, Jining First People’s Hospital, Shandong First Medical University, Jining, China Shandong Provincial Key Medical and Health Laboratory of Neuroinjury and Repair, Jining First People’s Hospital, Jining, China Department of Neurology, Zhongshan City People’s Hospital, Zhongshan, China Imaging Center, Zhongshan City People’s Hospital, Zhongshan, China Department of Neurosurgery, Affiliated Hospital of Jining Medical University, Jining, China The authors declare no competing interests. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Zhang, Wy., Wang, L., Zhang, T. et al. Cerebral endothelial cell-derived exosomes target injury sites to rescue cerebral energy crisis after traumatic brain injury.