{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T23:39:00Z","timestamp":1768001940357,"version":"3.49.0"},"reference-count":33,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T00:00:00Z","timestamp":1747180800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>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% \u00b1 3.74% and an entrapment efficiency of 78.78% \u00b1 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. <jats:italic>In vitro<\/jats:italic>, 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 \u00b1 1.16 to 4.20 \u00b1 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.<\/jats:p>","DOI":"10.3389\/fphar.2025.1543870","type":"journal-article","created":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T05:37:36Z","timestamp":1747201056000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["A ROS-responsive, aptamer-targeted graphene oxide nanocomposite for site-specific glutathione release in cerebral ischemia-reperfusion injury"],"prefix":"10.3389","volume":"16","author":[{"given":"Meiying","family":"Li","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lili","family":"Wei","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenxu","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiawen","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qiujie","family":"Lu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xianjue","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lee Yong","family":"Lim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jingxin","family":"Mo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,5,14]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1269581","DOI":"10.3389\/fphar.2023.1269581","article-title":"From imbalance to impairment: the central role of reactive oxygen species in oxidative stress-induced disorders and therapeutic exploration","volume":"14","author":"Afzal","year":"2023","journal-title":"Front. Pharmacol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"822","DOI":"10.3389\/fbioe.2020.00822","article-title":"The toxicity phenomenon and the related occurrence in metal and metal oxide nanoparticles: a brief review from the biomedical perspective","volume":"8","author":"Attarilar","year":"2020","journal-title":"Front. Bioeng. Biotechnol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"2506","DOI":"10.1002\/ejoc.202100240","article-title":"RGD peptide-drug conjugates as effective dual targeting platforms: recent advances","volume":"2021","author":"Battistini","year":"2021","journal-title":"Eur. J. Org. Chem."},{"key":"B4","doi-asserted-by":"publisher","first-page":"e202318665","DOI":"10.1002\/anie.202318665","article-title":"Development of better aptamers: structured library approaches, selection methods, and chemical modifications","volume":"63","author":"Brown","year":"2024","journal-title":"Angew. Chem. Int. Ed."},{"key":"B5","doi-asserted-by":"publisher","first-page":"1002285","DOI":"10.3389\/fbioe.2022.1002285","article-title":"Aptamer-based applications for cardiovascular disease","volume":"10","author":"Chen","year":"2022","journal-title":"Front. Bioeng. Biotechnol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"2989","DOI":"10.3390\/ijms22062989","article-title":"Functionalized reduced Graphene oxide as a versatile tool for cancer therapy","volume":"22","author":"Dash","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"B7","doi-asserted-by":"publisher","first-page":"e17488","DOI":"10.1016\/j.heliyon.2023.e17488","article-title":"Advances in drug delivery systems, challenges and future directions","volume":"9","author":"Ezike","year":"2023","journal-title":"Heliyon"},{"key":"B8","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1038\/s41572-022-00377-3","article-title":"Chronic wounds","volume":"8","author":"Falanga","year":"2022","journal-title":"Nat. Rev. Dis. Prim."},{"key":"B9","doi-asserted-by":"publisher","first-page":"1139","DOI":"10.3390\/biology12081139","article-title":"Cellular and molecular pathophysiology of traumatic brain injury: what have we learned so far?","volume":"12","author":"Freire","year":"2023","journal-title":"Biol. (Basel)"},{"key":"B10","doi-asserted-by":"publisher","first-page":"1685","DOI":"10.1177\/0271678X19874295","article-title":"Cerebrovascular effects of endothelin-1 investigated using high-resolution magnetic resonance imaging in healthy volunteers","volume":"40","author":"Hougaard","year":"2020","journal-title":"J. Cereb. Blood Flow. Metab."},{"key":"B11","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1021\/acsnano.1c07205","article-title":"Bioactive nanoenzyme reverses oxidative damage and endoplasmic reticulum stress in neurons under ischemic stroke","volume":"16","author":"Huang","year":"2022","journal-title":"ACS Nano"},{"key":"B12","doi-asserted-by":"publisher","first-page":"2534","DOI":"10.1039\/d1nr08144f","article-title":"Green approaches for the synthesis of metal and metal oxide nanoparticles using microbial and plant extracts","volume":"14","author":"Jeevanandam","year":"2022","journal-title":"Nanoscale"},{"key":"B13","doi-asserted-by":"publisher","first-page":"5305","DOI":"10.1021\/jacs.3c12002","article-title":"A water-stable boronate ester cage","volume":"146","author":"Kirchner","year":"2024","journal-title":"J. Am. Chem. Soc."},{"key":"B14","doi-asserted-by":"publisher","first-page":"2870","DOI":"10.1039\/d1cc03817f","article-title":"Fibrinogen aptamer functionalized gold-coated iron-oxide nanoparticles for targeted imaging of thrombi","volume":"58","author":"Koudrina","year":"2022","journal-title":"Chem. Commun."},{"key":"B15","doi-asserted-by":"publisher","first-page":"2737","DOI":"10.1021\/acs.bioconjchem.0c00525","article-title":"Assessment of aptamer-targeted contrast agents for monitoring of blood clots in computed tomography and fluoroscopy imaging","volume":"31","author":"Koudrina","year":"2020","journal-title":"Bioconjugate Chem."},{"key":"B16","doi-asserted-by":"publisher","first-page":"15021","DOI":"10.1039\/c2jm32307a","article-title":"Synthesis of partially hydrogenated graphene and brominated graphene","volume":"22","author":"Li","year":"2012","journal-title":"J. Mater. Chem."},{"key":"B17","doi-asserted-by":"publisher","first-page":"113312","DOI":"10.1016\/j.eurpolymj.2024.113312","article-title":"Dual network hydrogel sensors based on borate ester bond: multifunctional performance in high conductivity, stretchability, mechanical strength, and anti-freezing properties","volume":"217","author":"Liu","year":"2024","journal-title":"Eur. Polym. J."},{"key":"B18","doi-asserted-by":"publisher","first-page":"1469677","DOI":"10.3389\/fchem.2024.1469677","article-title":"Highlighting multicomponent reactions as an efficient and facile alternative route in the chemical synthesis of organic-based molecules: a tremendous growth in the past 5 years","volume":"12","author":"Mohlala","year":"2024","journal-title":"Front. Chem."},{"key":"B19","doi-asserted-by":"publisher","first-page":"101894","DOI":"10.1016\/j.mtchem.2023.101894","article-title":"Exploring the emerging trends in the synthesis and theranostic paradigms of cerium oxide nanoparticles (CeONPs): a comprehensive review","volume":"35","author":"Nag","year":"2024","journal-title":"Mater. Today Chem."},{"key":"B20","doi-asserted-by":"publisher","first-page":"e1701028","DOI":"10.1126\/sciadv.1701028","article-title":"Borate esters: simple catalysts for the sustainable synthesis of complex amides","volume":"3","author":"Sabatini","year":"2017","journal-title":"Sci. Adv."},{"key":"B21","doi-asserted-by":"publisher","first-page":"113862","DOI":"10.1016\/j.cattod.2022.08.004","article-title":"Zeta potential as a tool for functional materials development","volume":"423","author":"Serrano-Lotina","year":"2023","journal-title":"Catal. Today"},{"key":"B22","doi-asserted-by":"publisher","first-page":"121428","DOI":"10.1016\/j.biomaterials.2022.121428","article-title":"Immunogenic nanomedicine based on GSH-responsive nanoscale covalent organic polymers for chemo-sonodynamic therapy","volume":"283","author":"Shen","year":"2022","journal-title":"Biomaterials"},{"key":"B23","doi-asserted-by":"publisher","first-page":"2141","DOI":"10.1161\/01.str.29.10.2141","article-title":"YM872, a highly water-soluble AMPA receptor antagonist, preserves the hemodynamic penumbra and reduces brain injury after permanent focal ischemia in rats","volume":"29","author":"Shimizu-Sasamata","year":"1998","journal-title":"Stroke"},{"key":"B24","doi-asserted-by":"publisher","first-page":"2372","DOI":"10.3390\/ijms25042372","article-title":"Innovative insights into traumatic brain injuries: biomarkers and new pharmacological targets","volume":"25","author":"Silvestro","year":"2024","journal-title":"Int. J. Mol. Sci."},{"key":"B25","doi-asserted-by":"publisher","first-page":"418","DOI":"10.1038\/s41392-023-01642-x","article-title":"Smart nanoparticles for cancer therapy","volume":"8","author":"Sun","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"B26","doi-asserted-by":"publisher","first-page":"102310","DOI":"10.1016\/j.nantod.2024.102310","article-title":"Blood-brain barrier penetrating nanosystems enable synergistic therapy of glioblastoma","volume":"56","author":"Sun","year":"2024","journal-title":"Nano Today"},{"key":"B27","first-page":"153","article-title":"Endothelial nitric oxide synthase (eNOS) and the cardiovascular system: in physiology and in disease states","volume":"15","author":"Tran","year":"2022","journal-title":"Am. J. Biomed. Sci. Res."},{"key":"B28","doi-asserted-by":"publisher","first-page":"2208018","DOI":"10.1002\/adma.202208018","article-title":"Overcoming the blood\u2013brain barrier for gene therapy via systemic administration of GSH-responsive silica nanocapsules","volume":"35","author":"Wang","year":"2023","journal-title":"Adv. Mater."},{"key":"B29","doi-asserted-by":"publisher","first-page":"704077","DOI":"10.3389\/fbioe.2021.704077","article-title":"Systematic evolution of ligands by exponential enrichment Technologies and aptamer-based applications: recent progress and challenges in precision medicine of infectious diseases","volume":"9","author":"Xu","year":"2021","journal-title":"Front. Bioeng. Biotechnol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1186\/s12951-020-00703-5","article-title":"Novel drug delivery systems targeting oxidative stress in chronic obstructive pulmonary disease: a review","volume":"18","author":"Xu","year":"2020","journal-title":"J. Nanobiotechnol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"2199","DOI":"10.4103\/NRR.NRR-D-23-01985","article-title":"Neuroprotective potential for mitigating ischemia-reperfusion-induced damage","volume":"20","author":"Ye","year":"2025","journal-title":"Neural Regen. Res."},{"key":"B32","doi-asserted-by":"publisher","first-page":"1356112","DOI":"10.3389\/fphar.2024.1356112","article-title":"Systematic review of melatonin in cerebral ischemia-reperfusion injury: critical role and therapeutic opportunities","volume":"15","author":"Zhang","year":"","journal-title":"Front. Pharmacol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1038\/s41392-023-01688-x","article-title":"Ischemia-reperfusion injury: molecular mechanisms and therapeutic targets","volume":"9","author":"Zhang","year":"","journal-title":"Signal Transduct. Target. Ther."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1543870\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T05:37:37Z","timestamp":1747201057000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1543870\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,14]]},"references-count":33,"alternative-id":["10.3389\/fphar.2025.1543870"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2025.1543870","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,14]]},"article-number":"1543870"}}