What question did this study set out to answer?

To investigate the potential of exosome-delivered circBDNF in promoting repair after spinal cord injury through the PI3K/AKT/mTOR pathway.

March 21, 2026Open Access

Exosome‐Loaded Engineered circBDNF Promotes Spinal Cord Injury Repair Through the PI3K / AKT / mTOR Signaling Axis

Key Points

To investigate the potential of exosome-delivered circBDNF in promoting repair after spinal cord injury through the PI3K/AKT/mTOR pathway.
Engineered circBDNF was transfected into HEK293T cells to create circBDNF-loaded exosomes.
Exosomes were characterized using various techniques including transmission electron microscopy and Western blotting.
In vitro experiments assessed cell viability and other metrics in an oxygen-glucose deprivation model.
In vivo studies utilized a T10 spinal cord injury mouse model for efficacy analysis using several behavioral and histological assessments.
CircBDNF-exo treatment led to significant increases in BDNF expression and cell viability in vitro.
Reduced apoptosis and oxidative stress levels were observed in treated HT22 cells.
In vivo, treated mice showed improved motor function and coordination as indicated by Basso Mouse Scale scores and electrophysiological measures.
Histological assessments revealed enhanced axonal regeneration and decreased injury markers in the spinal cord.

Abstract

ABSTRACT Background The brain‐derived neurotrophic factor (BDNF) is a potent neuroprotective factor; however, its large molecular size limits its ability to cross structural barriers such as the blood–spinal cord barrier. This study explores the therapeutic potential of exosome‐mediated delivery of engineered circular BDNF (circBDNF) to promote spinal cord injury (SCI) repair through activation of the PI3K/AKT/mTOR signaling pathway. Methods A synthetic circBDNF sequence encoding BDNF was used to construct a circBDNF overexpression plasmid, which was transfected into HEK293T cells to generate circBDNF‐loaded exosomes (circBDNF‐EXO). These exosomes were characterized via transmission electron microscopy, nanoparticle tracking analysis, and Western blotting. In vitro, the protective effects of circBDNF‐EXO were evaluated in an oxygen–glucose deprivation/reperfusion (OGD) injury model in HT22 cells, focusing on cell viability, reactive oxygen species (ROS) levels, apoptosis, inflammation, and signaling pathways. In vivo, a T10 SCI mouse model was employed to assess therapeutic efficacy, using behavioral, electrophysiological, histological, and molecular analyses. Results In vitro, circBDNF‐EXO treatment significantly increased BDNF expression, enhanced cell viability, reduced ROS levels, mitigated inflammation, and inhibited apoptosis in HT22 cells following OGD injury. In vivo, administration of circBDNF‐EXO resulted in improved motor function recovery, evidenced by increased Basso Mouse Scale scores, enhanced gait coordination, and better motor‐evoked potentials. Histological analyses demonstrated elevated BDNF expression, decreased apoptosis, reduced oxidative stress, and enhanced axonal regeneration in the injured spinal cord. Mechanistically, circBDNF‐EXO activated TrkB receptors and upregulated the PI3K/AKT/mTOR signaling pathway, as confirmed by Western blot analysis. Conclusion Exosome‐mediated delivery of circBDNF promotes SCI repair by activating the PI3K/AKT/mTOR pathway, suppressing apoptosis, oxidative stress, and inflammation, and enhancing axonal regeneration. This innovative approach holds substantial promise for SCI treatment and deserves further exploration in preclinical and clinical studies.

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