{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T20:43:35Z","timestamp":1791665015689,"version":"4.3.4"},"reference-count":45,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2022,4,15]],"date-time":"2022-04-15T00:00:00Z","timestamp":1649980800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Key Research and Development Program of China Project","award":["2018YFA0108001\/2021YFA1100012"],"award-info":[{"award-number":["2018YFA0108001\/2021YFA1100012"]}]}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["Cells"],"abstract":"<jats:p>Overcoming the lack of drugs for the treatment of traumatic brain injury (TBI) has long been a major challenge for the pharmaceutical industry. MiRNAs have emerged as potential targets for progress assessment and intervention against TBI. The brain-enriched miRNA let-7i has been proposed as an ideal candidate biomarker for TBI, but its regulatory roles in brain injury remain largely unknown. Here, we find that the expression of let-7i is significantly downregulated in the early stages of a hippocampal stab wound injury. The noninvasive intranasal administration of let-7i agomir significantly improves cognitive function and suppresses neuroinflammation, glial scar formation, and neuronal apoptosis in TBI mice. Mechanically, STING is a direct downstream target of let-7i after brain injury. Furthermore, the intranasal delivery of let-7i agomir can also effectively inhibit STING and is beneficial for inflammation resolution and neuronal survival in a mouse model of pial vessel disruption stroke. Consequently, let-7i agomir is a promising candidate for clinical application as a chemically engineered oligonucleotides-based therapeutic for brain injury.<\/jats:p>","DOI":"10.3390\/cells11081348","type":"journal-article","created":{"date-parts":[[2022,4,16]],"date-time":"2022-04-16T07:42:41Z","timestamp":1650094961000},"page":"1348","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Intranasal Administration of Agomir-let-7i Improves Cognitive Function in Mice with Traumatic Brain Injury"],"prefix":"10.3390","volume":"11","author":[{"given":"Xuan-Cheng","family":"He","sequence":"first","affiliation":[{"name":"State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China"},{"name":"Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China"},{"name":"Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China"},{"name":"Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China"},{"name":"Savaid Medical School, University of Chinese Academy of Sciences, Beijing 100049, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong-Zhen","family":"Du","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China"},{"name":"Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China"},{"name":"Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang-Mei","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China"},{"name":"Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China"},{"name":"Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China"},{"name":"Savaid Medical School, University of Chinese Academy of Sciences, Beijing 100049, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhao-Qian","family":"Teng","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China"},{"name":"Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China"},{"name":"Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China"},{"name":"Savaid Medical School, University of Chinese Academy of Sciences, Beijing 100049, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,4,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1093\/brain\/awaa321","article-title":"The synapse in traumatic brain injury","volume":"144","author":"Jamjoom","year":"2021","journal-title":"Brain"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1016\/j.anclin.2016.04.011","article-title":"Neuropathophysiology of Brain Injury","volume":"34","author":"Quillinan","year":"2016","journal-title":"Anesthesiol. Clin."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"875","DOI":"10.3389\/fneur.2019.00875","article-title":"Gut Microbiota as a Therapeutic Target to Ameliorate the Biochemical, Neuroanatomical, and Behavioral Effects of Traumatic Brain Injuries","volume":"10","author":"Rice","year":"2019","journal-title":"Front. Neurol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1007\/s11940-002-0004-6","article-title":"Cognitive Impairment Following Traumatic Brain Injury","volume":"4","author":"Arciniegas","year":"2002","journal-title":"Curr. Treat. Options Neurol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"S193","DOI":"10.1038\/nature16035","article-title":"Global neurotrauma research challenges and opportunities","volume":"527","author":"Rubiano","year":"2015","journal-title":"Nature"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Schepici, G., Silvestro, S., Bramanti, P., and Mazzon, E. (2020). Traumatic Brain Injury and Stem Cells: An Overview of Clinical Trials, the Current Treatments and Future Therapeutic Approaches. Medicina, 56.","DOI":"10.3390\/medicina56030137"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1038\/s41420-020-00325-8","article-title":"SerpinA3N deficiency deteriorates impairments of learning and memory in mice following hippocampal stab injury","volume":"6","author":"Wang","year":"2020","journal-title":"Cell Death Discov."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1749","DOI":"10.4103\/1673-5374.219025","article-title":"MicroRNAs as diagnostic markers and therapeutic targets for traumatic brain injury","volume":"12","author":"Martinez","year":"2017","journal-title":"Neural Regen. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"429","DOI":"10.3389\/fneur.2018.00429","article-title":"MicroRNA Signature of Traumatic Brain Injury: From the Biomarker Discovery to the Point-of-Care","volume":"9","author":"Yakoub","year":"2018","journal-title":"Front. Neurol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1007\/s13238-015-0212-y","article-title":"Biogenesis and regulation of the let-7 miRNAs and their functional implications","volume":"7","author":"Lee","year":"2016","journal-title":"Protein Cell"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1379","DOI":"10.1089\/neu.2011.2146","article-title":"MicroRNA let-7i is a promising serum biomarker for blast-induced traumatic brain injury","volume":"29","author":"Balakathiresan","year":"2012","journal-title":"J. Neurotrauma"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.brainres.2018.01.032","article-title":"MicroRNA let-7c-5p improves neurological outcomes in a murine model of traumatic brain injury by suppressing neuroinflammation and regulating microglial activation","volume":"1685","author":"Lv","year":"2018","journal-title":"Brain Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"6542","DOI":"10.4049\/jimmunol.1202496","article-title":"MicroRNA let-7c regulates macrophage polarization","volume":"190","author":"Banerjee","year":"2013","journal-title":"J. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e56709","DOI":"10.1371\/journal.pone.0056709","article-title":"Let-7b is involved in the inflammation and immune responses associated with Helicobacter pylori infection by targeting Toll-like receptor 4","volume":"8","author":"Teng","year":"2013","journal-title":"PLoS ONE"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1977","DOI":"10.1038\/emboj.2011.94","article-title":"Analysis of the host microRNA response to Salmonella uncovers the control of major cytokines by the let-7 family","volume":"30","author":"Schulte","year":"2011","journal-title":"EMBO J."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1016\/j.stem.2015.08.002","article-title":"Adult Neural Stem Cells from the Subventricular Zone Give Rise to Reactive Astrocytes in the Cortex after Stroke","volume":"17","author":"Faiz","year":"2015","journal-title":"Cell Stem Cell"},{"key":"ref_17","first-page":"4440","article-title":"Intranasal administration of CNS therapeutics to awake mice","volume":"74","author":"Hanson","year":"2013","journal-title":"J. Vis. Exp."},{"key":"ref_18","first-page":"57648","article-title":"Quantifying Microglia Morphology from Photomicrographs of Immunohistochemistry Prepared Tissue Using ImageJ","volume":"136","author":"Young","year":"2018","journal-title":"J. Vis. Exp."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1232","DOI":"10.7150\/thno.48761","article-title":"M2 microglial small extracellular vesicles reduce glial scar formation via the miR-124\/STAT3 pathway after ischemic stroke in mice","volume":"11","author":"Li","year":"2021","journal-title":"Theranostics"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1016\/j.stem.2010.02.017","article-title":"Epigenetic regulation of miR-184 by MBD1 governs neural stem cell proliferation and differentiation","volume":"6","author":"Liu","year":"2010","journal-title":"Cell Stem Cell"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1689","DOI":"10.1038\/s41593-018-0261-7","article-title":"Partial loss of psychiatric risk gene Mir137 in mice causes repetitive behavior and impairs sociability and learning via increased Pde10a","volume":"21","author":"Cheng","year":"2018","journal-title":"Nat. Neurosci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"109380","DOI":"10.1016\/j.jneumeth.2021.109380","article-title":"Mouse model of voluntary movement deficits induced by needlestick injuries to the primary motor cortex","volume":"365","author":"Liu","year":"2022","journal-title":"J. Neurosci. Methods."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e521","DOI":"10.1038\/tp.2015.17","article-title":"Altered hippocampal-dependent memory and motor function in neuropilin 2-deficient mice","volume":"5","author":"Shiflett","year":"2015","journal-title":"Transl. Psychiatry"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1050","DOI":"10.1038\/npp.2013.1","article-title":"Impaired hippocampus-dependent and facilitated striatum-dependent behaviors in mice lacking the delta opioid receptor","volume":"38","author":"Rezai","year":"2013","journal-title":"Neuropsychopharmacology"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Attar, A., Liu, T., Chan, W.T., Hayes, J., Nejad, M., Lei, K., and Bitan, G. (2013). A shortened Barnes maze protocol reveals memory deficits at 4-months of age in the triple-transgenic mouse model of Alzheimer\u2019s disease. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0080355"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"eaaz7070","DOI":"10.1126\/sciadv.aaz7070","article-title":"Let-7 derived from endometrial extracellular vesicles is an important inducer of embryonic diapause in mice","volume":"6","author":"Liu","year":"2020","journal-title":"Sci. Adv."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1016\/j.omtn.2019.10.002","article-title":"Intranasal Administration of miR-146a Agomir Rescued the Pathological Process and Cognitive Impairment in an AD Mouse Model","volume":"18","author":"Mai","year":"2019","journal-title":"Mol. Ther. Nucleic Acids"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1186\/s12974-016-0738-9","article-title":"Neurogenic inflammation after traumatic brain injury and its potentiation of classical inflammation","volume":"13","author":"Corrigan","year":"2016","journal-title":"J. Neuroinflamm."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1016\/j.neuropharm.2018.08.004","article-title":"Pathophysiology and treatment of cerebral edema in traumatic brain injury","volume":"145","author":"Jha","year":"2019","journal-title":"Neuropharmacology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2600","DOI":"10.1007\/s12035-020-01904-7","article-title":"cGAS\/STING Pathway Activation Contributes to Delayed Neurodegeneration in Neonatal Hypoxia-Ischemia Rat Model: Possible Involvement of LINE-1","volume":"57","author":"Gamdzyk","year":"2020","journal-title":"Mol. Neurobiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2384","DOI":"10.1523\/JNEUROSCI.2881-19.2020","article-title":"PERK-STING Signaling Drives Neuroinflammation in Traumatic Brain Injury","volume":"40","author":"Chin","year":"2020","journal-title":"J. Neurosci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1038\/s41586-020-2625-x","article-title":"C9orf72 in myeloid cells suppresses STING-induced inflammation","volume":"585","author":"McCauley","year":"2020","journal-title":"Nature"},{"key":"ref_33","unstructured":"Heidenreich, K.A. (2017). New Therapeutics for Traumatic Brain Injury: Prevention of Secondary Brain Damage and Enhancement of Repair and Regeneration, Elsevier."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/j.neuroscience.2017.10.046","article-title":"The Role of MicroRNA in Traumatic Brain Injury","volume":"367","author":"Pan","year":"2017","journal-title":"Neuroscience"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1125","DOI":"10.1177\/0271678X18773871","article-title":"MicroRNA-based therapeutics in central nervous system injuries","volume":"38","author":"Sun","year":"2018","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"319","DOI":"10.2174\/1570159X17666191113100808","article-title":"MicroRNAs: The New Challenge for Traumatic Brain Injury Diagnosis","volume":"18","author":"Pinchi","year":"2020","journal-title":"Curr. Neuropharmacol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"16352","DOI":"10.1002\/jcb.29130","article-title":"Exosomal microRNA and stroke: A review","volume":"120","author":"Ghoreishy","year":"2019","journal-title":"J. Cell Biochem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"856","DOI":"10.1002\/jcp.25787","article-title":"MicroRNA: Relevance to stroke diagnosis, prognosis, and therapy","volume":"233","author":"Mirzaei","year":"2018","journal-title":"J. Cell Physiol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"215","DOI":"10.3389\/fnins.2020.00215","article-title":"MicroRNA Let-7i Is a Promising Serum Biomarker for Post-stroke Cognitive Impairment and Alleviated OGD-Induced Cell Damage in vitro by Regulating Bcl-2","volume":"14","author":"Wang","year":"2020","journal-title":"Front. Neurosci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1016\/j.tcb.2008.07.007","article-title":"The let-7 family of microRNAs","volume":"18","author":"Roush","year":"2008","journal-title":"Trends Cell Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1038\/nrneurol.2017.13","article-title":"The far-reaching scope of neuroinflammation after traumatic brain injury","volume":"13","author":"Simon","year":"2017","journal-title":"Nat. Rev. Neurol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"e13468","DOI":"10.1111\/acel.13468","article-title":"Inhibition of the cGAS-STING pathway ameliorates the premature senescence hallmarks of Ataxia-Telangiectasia brain organoids","volume":"20","author":"Aguado","year":"2021","journal-title":"Aging Cell"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1186\/s12974-018-1354-7","article-title":"STING-mediated type-I interferons contribute to the neuroinflammatory process and detrimental effects following traumatic brain injury","volume":"15","author":"Abdullah","year":"2018","journal-title":"J. Neuroinflamm."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"9644","DOI":"10.7150\/thno.47651","article-title":"HDAC3 inhibition ameliorates ischemia\/reperfusion-induced brain injury by regulating the microglial cGAS-STING pathway","volume":"10","author":"Liao","year":"2020","journal-title":"Theranostics"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"e2105465118","DOI":"10.1073\/pnas.2105465118","article-title":"STING inhibitors target the cyclic dinucleotide binding pocket","volume":"118","author":"Hong","year":"2021","journal-title":"Proc. Natl. Acad. Sci. USA"}],"updated-by":[{"DOI":"10.3390\/cells11203253","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2022,4,15]],"date-time":"2022-04-15T00:00:00Z","timestamp":1649980800000}}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/8\/1348\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,3]],"date-time":"2025-08-03T14:07:08Z","timestamp":1754230028000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/8\/1348"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4,15]]},"references-count":45,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2022,4]]}},"alternative-id":["cells11081348"],"URL":"https:\/\/doi.org\/10.3390\/cells11081348","relation":{"correction":[{"id-type":"doi","id":"10.3390\/cells11203253","asserted-by":"object"}]},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,4,15]]}}}