A ROS-responsive, aptamer-targeted graphene oxide nanocomposite for site-specific glutathione release in cerebral ischemia-reperfusion injury

Meiying Li; Lili Wei; Wenxu Liu; Jiawen Wang; Qiujie Lu; Xianjue Chen; Lee Yong Lim; Jingxin Mo

doi:10.3389/fphar.2025.1543870

A ROS-responsive, aptamer-targeted graphene oxide nanocomposite for site-specific glutathione release in cerebral ischemia-reperfusion injury

Front Pharmacol. 2025 May 14:16:1543870. doi: 10.3389/fphar.2025.1543870. eCollection 2025.

Authors

Meiying Li^#^{1

2}, Lili Wei^#³, Wenxu Liu², Jiawen Wang¹, Qiujie Lu⁴, Xianjue Chen⁵, Lee Yong Lim⁶, Jingxin Mo^{1

7

8

9}

Affiliations

¹ Lab of Neurology, The Affiliated Hospital of Guilin Medical University, Guilin, China.
² School of Pharmacy, Guilin Medical University, Guilin, China.
³ Pharmaceutical Clinical Trial Laboratory, The Affiliated Hospital of Guilin Medical University, Guilin, China.
⁴ School of Clinical Medicine, Guilin Medical University, Guilin, China.
⁵ School of Environmental and Life Sciences, University of Newcastle, Callaghan, NSW, Australia.
⁶ School of Allied Health, University of Western Australia, Perth, WA, Australia.
⁷ Clinical Research Center for Neurological Diseases of Guangxi Province, The Affiliated Hospital of Guilin Medical University, Guilin, China.
⁸ Guangxi Key Laboratory of Big Data Intelligent Cloud Management for Neurological Diseases, Guilin Medical University, Guilin, China.
⁹ Guangxi Engineering Research Center of Digital Medicine and Clinical Translation, Guilin Medical University, Guilin, China.

^# Contributed equally.

Abstract

Cerebral ischemia-reperfusion (I/R) injury is a major contributor to mortality and long-term disability worldwide, primarily due to excessive reactive oxygen species (ROS) generation after blood flow is restored. Although current treatments focus on reestablishing perfusion, they offer limited protection against the secondary ROS-mediated injury. Here, we report a multifunctional nanocomposite-graphene oxide loaded with glutathione (GSH) and functionalized with a fibrinogen-targeting aptamer (GO@GSH-FA)-capable of selectively releasing antioxidant cargo within the ischemic brain microenvironment. Characterization revealed a drug-loading capacity of 17.59% ± 3.74% and an entrapment efficiency of 78.78% ± 4.55%, highlighting the robust loading of GSH. The ROS-sensitive borate ester linker ensures that GSH is preferentially liberated in oxidative stress regions, while the fibrinogen aptamer actively targets fibrin-rich thrombotic sites. In vitro, GO@GSH-FA significantly restored viability in oxygen-glucose-deprived SH-SY5Y cells (from 31% up to near control levels), reduced inflammatory cytokines, and lowered intracellular ROS. In a Endothelin-1 (ET-1) induced cortical ischemia model, GO@GSH-FA led to a marked decrease in neurological deficit scores (from 7.20 ± 1.16 to 4.20 ± 0.98) and enhanced neuronal survival relative to untreated animals. Collectively, these findings underscore the promise of GO@GSH-FA as a targeted, ROS-responsive platform for mitigating cerebral I/R injury.

Keywords: cerebral ischemia-reperfusion injury; fibrinogen aptamer; glutathione; graphene oxide; oxidative stress.