{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T19:33:06Z","timestamp":1786649586134,"version":"build-2736575974"},"reference-count":121,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"10","license":[{"start":{"date-parts":[[2025,12,30]],"date-time":"2025-12-30T00:00:00Z","timestamp":1767052800000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0 http:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:p>Neonatal hypoxic-ischemic encephalopathy is the leading cause of brain injury in term infants worldwide and disproportionately affects low- and middle-income communities. Therapeutic hypothermia, the standard of care for hypoxic-ischemic encephalopathy in high-resourced settings, has no effect on morbidity and increases mortality after hypoxic-ischemic encephalopathy in low- and middle-income settings. Intranasal administration offers the opportunity to deliver more accessible treatments for all babies with neonatal hypoxic-ischemic encephalopathy due to lower resource needs, ease of administration, and the capacity to directly target the brain. We reviewed preclinical literature concerning intranasal treatments for hypoxic-ischemic encephalopathy and developed a novel semi-quantitative index ranking intranasal therapies for their potential for further development as biologically plausible, effective, and accessible treatments for hypoxic-ischemic encephalopathy. We searched PubMed and Google Scholar for peer-reviewed articles on intranasal therapies for hypoxic-ischemic encephalopathy using the mesh phrases \u201cNeonatal hypoxic-ischemic encephalopathy intranasal\u201d and \u201cNeonatal brain intranasal.\u201d Sixty-two studies were included that described thirty-four unique intranasal therapies. Neonatal intranasal therapies have been widely studied in small animal models, infrequently in large animals, and only recently in human clinical trials. Our semi-quantitative ranking revealed cell-based therapies as potentially the most effective and developed intranasal therapy in animal models of hypoxic-ischemic encephalopathy, though the pharmaceutical support compulsory to current cell-based treatments limits their accessibility in low-resourced settings. Intranasal therapies for neonatal hypoxic-ischemic encephalopathy have both feasibility and neuroprotective potential for safe, effective, and accessible treatment of hypoxic-ischemic encephalopathy. Additional research is needed for translation to humans. Future investigation should emphasize appropriate animal modeling with pharmaceutics and cells, combined with an evaluation of the brain connectome and neurobehavioral outcomes.<\/jats:p>","DOI":"10.4103\/nrr.nrr-d-25-01036","type":"journal-article","created":{"date-parts":[[2025,12,30]],"date-time":"2025-12-30T11:00:08Z","timestamp":1767092408000},"page":"4617-4622","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":0,"title":["Intranasal therapies for neonatal hypoxic-ischemic encephalopathy"],"prefix":"10.4103","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-1000-7934","authenticated-orcid":false,"given":"Andrew S.","family":"Cavanagh","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Division of Neonatology, Johns Hopkins School of Medicine, Baltimore, MD, USA"},{"name":"Undergraduate Programs in Neuroscience and Molecular and Cellular Biology, Johns Hopkins Krieger School of Arts and Sciences, Baltimore, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin I.","family":"Sollinger","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Neonatology, Johns Hopkins School of Medicine, Baltimore, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nazli","family":"Kuter","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Neonatology, Johns Hopkins School of Medicine, Baltimore, MD, USA"},{"name":"Department of Neurology and Developmental Medicine, Kennedy Krieger Institute, Baltimore, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khyzer","family":"Aziz","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Neonatology, Johns Hopkins School of Medicine, Baltimore, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria","family":"Turnbill","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Neonatology, Johns Hopkins School of Medicine, Baltimore, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lee J.","family":"Martin","sequence":"additional","affiliation":[{"name":"Departments of Pathology, Neuroscience, and Anesthesiology & Critical Care Medicine, Johns Hopkins School of Medicine, Baltimore MD, USA"},{"name":"Pathobiology Graduate Training Program, Johns Hopkins School of Medicine, Baltimore, MD. 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