{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T13:17:27Z","timestamp":1787750247897,"version":"build-2784847793"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T00:00:00Z","timestamp":1787702400000},"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. Neurol."],"abstract":"<jats:p>\n                    The development of ischemic stroke involves swiftly changing and spatially varied states, including oxidative burst, acidosis, hypoxia, endothelial dysfunction, blood-brain barrier disruption, neuroinflammation, and later tissue remodeling. This temporal structure is poorly matched by conventional single-dose neuroprotectants. Nanozyme-hydrogel systems that respond to stimuli provide a promising approach by integrating catalytic redox control with localized retention, lesion-adaptive mechanics, and release triggered by specific cues. This Mini Review critically examines the design logic of such systems for ischemic stroke. Initially, we categorize reactive oxygen and nitrogen species, low pH, hypoxia, thrombin, matrix metalloproteinases, and inflammatory signals as a pathological code for activating materials. Following this, we examine nanozyme catalytic modules, responsive hydrogel matrices, and integration approaches including encapsulation, anchoring,\n                    <jats:italic>in situ<\/jats:italic>\n                    assembly, and multi-input gating. Emphasis is on the phase-aligned management of the neurovascular unit, covering early reperfusion defense, endothelial stabilization, glial adjustment, angiogenesis, and neural reconfiguration. A key takeaway is that there is limited direct evidence of fully integrated nanozyme-hydrogel platforms specifically for stroke; the field largely relies on the intersection of advanced stroke nanozymes and responsive hydrogels. Consequently, we recommend translational benchmarks that emphasize phase-route alignment, exact catalytic activity, degradation tracking, production feasibility, and validation in various preclinical settings. Accordingly, this Mini Review is intended as a design framework for hypothesis generation and preclinical validation, rather than as evidence of clinical readiness.\n                  <\/jats:p>","DOI":"10.3389\/fneur.2026.1945621","type":"journal-article","created":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T12:17:25Z","timestamp":1787746645000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Stimuli-responsive nanozyme-hydrogel systems for ischemic stroke: toward spatiotemporal catalytic control of the neurovascular unit"],"prefix":"10.3389","volume":"17","author":[{"given":"Sen","family":"Yan","sequence":"first","affiliation":[{"name":"Qilu Medical University","place":["Zibo, China"]},{"name":"Hebei Normal University","place":["Shijiazhuang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohong","family":"Wang","sequence":"additional","affiliation":[{"name":"Qilu Medical University","place":["Zibo, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cai","family":"Li","sequence":"additional","affiliation":[{"name":"Qilu Medical University","place":["Zibo, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rong","family":"Wang","sequence":"additional","affiliation":[{"name":"Qilu Medical University","place":["Zibo, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,26]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"e316","DOI":"10.1161\/STR.0000000000000513","article-title":"2026 Guideline for the early management of patients with acute ischemic stroke: a guideline From the American heart Association\/American stroke association","volume":"57","author":"Prabhakaran","year":"2026","journal-title":"Stroke."},{"key":"B2","doi-asserted-by":"publisher","first-page":"116186","DOI":"10.1016\/j.bcp.2024.116186","article-title":"The role of oxidative stress in blood-brain barrier disruption during ischemic stroke: antioxidants in clinical trials","volume":"228","author":"Lochhead","year":"2024","journal-title":"Biochem Pharmacol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"460","DOI":"10.3390\/biology9120460","article-title":"Tissue acidosis associated with ischemic stroke to guide neuroprotective drug delivery","volume":"9","author":"T\u00f3th","year":"2020","journal-title":"Biology."},{"key":"B4","doi-asserted-by":"publisher","first-page":"105742","DOI":"10.1016\/j.phrs.2021.105742","article-title":"Hypoxia-inducible factor-1: regulatory mechanisms and drug development in stroke","volume":"170","author":"Pan","year":"2021","journal-title":"Pharmacol Res."},{"key":"B5","doi-asserted-by":"publisher","first-page":"2178","DOI":"10.1161\/STROKEAHA.123.042705","article-title":"The ever-evolving concept of the neurovascular unit","volume":"54","author":"Alkayed","year":"2023","journal-title":"Stroke."},{"key":"B6","doi-asserted-by":"publisher","first-page":"5571","DOI":"10.7150\/thno.99822","article-title":"Microenvironment-responsive nanosystems for ischemic stroke therapy","volume":"14","author":"Wu","year":"2024","journal-title":"Theranostics."},{"key":"B7","doi-asserted-by":"publisher","first-page":"1329959","DOI":"10.3389\/fbioe.2023.1329959","article-title":"Application of stimuli-responsive nanomedicines for the treatment of ischemic stroke","volume":"11","author":"Zhan","year":"2024","journal-title":"Front Bioeng Biotechnol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"2492","DOI":"10.7150\/thno.83370","article-title":"The applications of nanozymes in neurological diseases: from mechanism to design","volume":"13","author":"Zhang","year":"2023","journal-title":"Theranostics."},{"key":"B9","doi-asserted-by":"publisher","first-page":"16450","DOI":"10.1021\/acsnano.4c03425","article-title":"Nanozymes: potential therapies for reactive oxygen species overproduction and inflammation in ischemic stroke and traumatic brain injury","volume":"18","author":"Yang","year":"2024","journal-title":"ACS Nano."},{"key":"B10","doi-asserted-by":"publisher","first-page":"e2210144","DOI":"10.1002\/adma.202210144","article-title":"A thrombin-activated peptide-templated nanozyme for remedying ischemic stroke via thrombolytic and neuroprotective actions","volume":"36","author":"Wang","year":"2024","journal-title":"Adv Mater."},{"key":"B11","doi-asserted-by":"publisher","first-page":"2204025","DOI":"10.1002\/adfm.202204025","article-title":"Se-containing MOF coated dual-Fe-atom nanozymes with multi-enzyme cascade activities protect against cerebral ischemic reperfusion injury","volume":"32","author":"Tian","year":"2022","journal-title":"Adv Funct Mater."},{"key":"B12","doi-asserted-by":"publisher","first-page":"1122","DOI":"10.3390\/pharmaceutics14061122","article-title":"Transferrin-enabled blood-brain barrier crossing manganese-based nanozyme for rebalancing the reactive oxygen species level in ischemic stroke","volume":"14","author":"Zhao","year":"2022","journal-title":"Pharmaceutics."},{"key":"B13","doi-asserted-by":"publisher","first-page":"46213","DOI":"10.1021\/acsami.1c06449","article-title":"A Co-doped Fe3O4 nanozyme shows enhanced reactive oxygen and nitrogen species scavenging activity and ameliorates the deleterious effects of ischemic stroke","volume":"13","author":"Liu","year":"2021","journal-title":"ACS Appl Mater Interfaces."},{"key":"B14","doi-asserted-by":"publisher","first-page":"5510","DOI":"10.1021\/acsnano.3c10982","article-title":"Bioactive ceria nanoenzymes target mitochondria in reperfusion injury to treat ischemic stroke","volume":"18","author":"Liao","year":"2024","journal-title":"ACS Nano."},{"key":"B15","doi-asserted-by":"publisher","first-page":"113750","DOI":"10.1016\/j.jconrel.2025.113750","article-title":"Brain-targeting biomimetic nanozyme enhances neuroprotection in ischemic stroke by remodeling the neurovascular unit","volume":"382","author":"Song","year":"2025","journal-title":"J Control Release."},{"key":"B16","doi-asserted-by":"publisher","first-page":"158039","DOI":"10.1016\/j.cej.2024.158039","article-title":"An injectable extracellular matrix-mimicking conductive hydrogel for sequential treatment of ischemic stroke","volume":"502","author":"Wang","year":"2024","journal-title":"Chem Eng J."},{"key":"B17","doi-asserted-by":"publisher","first-page":"1112","DOI":"10.1016\/j.apsb.2025.01.005","article-title":"NO-releasing double-crosslinked responsive hydrogels accelerate the treatment and repair of ischemic stroke","volume":"15","author":"Guo","year":"2025","journal-title":"Acta Pharm Sin B."},{"key":"B18","doi-asserted-by":"publisher","first-page":"591","DOI":"10.1016\/j.jconrel.2024.03.050","article-title":"Remodeling brain pathological microenvironment to lessen cerebral ischemia injury by multifunctional injectable hydrogels","volume":"369","author":"Zhang","year":"2024","journal-title":"J Control Release."},{"key":"B19","doi-asserted-by":"publisher","first-page":"503","DOI":"10.4103\/NRR.NRR-D-23-01322","article-title":"A matrix metalloproteinase-responsive hydrogel system controls angiogenic peptide release for repair of cerebral ischemia\/reperfusion injury","volume":"20","author":"Liu","year":"2025","journal-title":"Neural Regen Res."},{"key":"B20","doi-asserted-by":"publisher","first-page":"142520","DOI":"10.1016\/j.cej.2023.142520","article-title":"Multifunctional injectable hydrogel promotes functional recovery after stroke by modulating microglial polarization, angiogenesis and neuroplasticity","volume":"464","author":"Ma","year":"2023","journal-title":"Chem Eng J."},{"key":"B21","doi-asserted-by":"publisher","first-page":"133671","DOI":"10.1016\/j.cej.2021.133671","article-title":"Dual-function hydrogels with sequential release of GSK3\u03b2 inhibitor and VEGF inhibit inflammation and promote angiogenesis after stroke","volume":"433","author":"Liu","year":"2022","journal-title":"Chem Eng J."},{"key":"B22","doi-asserted-by":"publisher","first-page":"9285","DOI":"10.1038\/s41467-025-64240-1","article-title":"Injectable micropore-forming microgel scaffold for neural progenitor cells transplantation and vascularization after stroke","volume":"16","author":"Wu","year":"2025","journal-title":"Nat Commun."},{"key":"B23","doi-asserted-by":"publisher","first-page":"37193","DOI":"10.1021\/acsami.3c06189","article-title":"Nanozyme-integrated thermoresponsive in situ forming hydrogel enhances mesenchymal stem cell viability and paracrine effect for efficient spinal cord repair","volume":"15","author":"Xu","year":"2023","journal-title":"ACS Appl Mater Interfaces."},{"key":"B24","doi-asserted-by":"publisher","first-page":"e2400272121","DOI":"10.1073\/pnas.2400272121","article-title":"Endothelial peroxiredoxin-4 is indispensable for blood-brain barrier integrity and long-term functional recovery after ischemic stroke","volume":"121","author":"Xu","year":"2024","journal-title":"Proc Natl Acad Sci USA."},{"key":"B25","doi-asserted-by":"publisher","first-page":"e13006","DOI":"10.1111\/bpa.13006","article-title":"Glycocalyx is critical for blood-brain barrier integrity by suppressing caveolin1-dependent endothelial transcytosis following ischemic stroke","volume":"32","author":"Zhu","year":"2022","journal-title":"Brain Pathol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"eadk2913","DOI":"10.1126\/sciadv.adk2913","article-title":"Regulation of blood-brain barrier integrity by Dmp1-expressing astrocytes through mitochondrial transfer","volume":"10","author":"Liu","year":"2024","journal-title":"Sci Adv"},{"key":"B27","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1186\/s13041-025-01244-4","article-title":"Microglia-astrocyte crosstalk following ischemic stroke","volume":"18","author":"Yang","year":"2025","journal-title":"Mol Brain."},{"key":"B28","doi-asserted-by":"publisher","first-page":"115131","DOI":"10.1016\/j.expneurol.2024.115131","article-title":"Astrogliosis and glial scar in ischemic stroke: focused on mechanism and treatment","volume":"385","author":"Chen","year":"2025","journal-title":"Exp Neurol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"114547","DOI":"10.1016\/j.expneurol.2023.114547","article-title":"Neural stem cell-derived exosomes-loaded adhesive hydrogel controlled-release promotes cerebral angiogenesis and neurological function in ischemic stroke","volume":"370","author":"Gu","year":"2023","journal-title":"Exp Neurol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"190","DOI":"10.1161\/STROKEAHA.123.043764","article-title":"drug delivery in stroke: improving therapeutic translation from the bench to the bedside","volume":"55","author":"Ronaldson","year":"2024","journal-title":"Stroke."},{"key":"B31","doi-asserted-by":"publisher","first-page":"4103","DOI":"10.1039\/D4TB02722A","article-title":"A T1 MRI detectable hyaluronic acid hydrogel for in vivo tracking after intracerebral injection in stroke","volume":"13","author":"Said","year":"2025","journal-title":"J Mater Chem B."},{"key":"B32","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1038\/s41529-024-00487-1","article-title":"review of biomaterial degradation assessment approaches employed in the biomedical field","volume":"8","author":"Mndlovu","year":"2024","journal-title":"npj Mater Degrad."},{"key":"B33","doi-asserted-by":"publisher","first-page":"eabq0997","DOI":"10.1126\/sciadv.abq0997","article-title":"Global trends in clinical trials involving engineered biomaterials","volume":"10","author":"Lele","year":"2024","journal-title":"Sci Adv"},{"key":"B34","doi-asserted-by":"publisher","first-page":"3063","DOI":"10.1161\/STROKEAHA.121.034947","article-title":"Consortium. Top priorities for cerebroprotective studies\u2014a paradigm shift: report from STAIR XI","volume":"52","author":"Lyden","year":"2021","journal-title":"Stroke"},{"key":"B35","doi-asserted-by":"publisher","first-page":"1802","DOI":"10.1161\/STROKEAHA.121.038047","article-title":"The stroke preclinical assessment network: rationale, design, feasibility, and stage 1 results","volume":"53","author":"Lyden","year":"2022","journal-title":"Stroke."},{"key":"B36","doi-asserted-by":"publisher","first-page":"eadg8656","DOI":"10.1126\/scitranslmed.adg8656","article-title":"A multi-laboratory preclinical trial in rodents to assess treatment candidates for acute ischemic stroke","volume":"15","author":"Lyden","year":"2023","journal-title":"Sci Transl Med"},{"key":"B37","doi-asserted-by":"publisher","first-page":"e12","DOI":"10.1161\/STROKEAHA.125.052056","article-title":"Preclinical Ischemic Stroke Multicenter Trials (PRISM) collective statement: opportunities, challenges, and recommendations for a new era","volume":"57","author":"Ayata","year":"2026","journal-title":"Stroke."},{"key":"B38","doi-asserted-by":"publisher","first-page":"924","DOI":"10.3389\/fneur.2019.00924","article-title":"The potential of biomaterial-based approaches as therapies for ischemic stroke: a systematic review and meta-analysis of pre-clinical studies","volume":"10","author":"Bolan","year":"2019","journal-title":"Front Neurol."},{"key":"B39","doi-asserted-by":"publisher","first-page":"117564","DOI":"10.1016\/j.biopha.2024.117564","article-title":"Advances in nanoparticle-based therapeutics for ischemic stroke: enhancing drug delivery and efficacy","volume":"180","author":"Ji","year":"2024","journal-title":"Biomed Pharmacother."},{"key":"B40","doi-asserted-by":"publisher","first-page":"6817","DOI":"10.1038\/s41467-025-62063-8","article-title":"Nanozymes expanding the boundaries of biocatalysis","volume":"16","author":"Zhang","year":"2025","journal-title":"Nat Commun."}],"container-title":["Frontiers in Neurology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2026.1945621\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T12:17:26Z","timestamp":1787746646000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2026.1945621\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,26]]},"references-count":40,"alternative-id":["10.3389\/fneur.2026.1945621"],"URL":"https:\/\/doi.org\/10.3389\/fneur.2026.1945621","relation":{},"ISSN":["1664-2295"],"issn-type":[{"value":"1664-2295","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,26]]},"article-number":"1945621"}}