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There are significant physiological and anatomical differences in the nasal cavity, olfactory area, and airflow reaching the olfactory epithelium between humans and experimentally studied species that should be considered when extrapolating experimental results to humans. Mucus, transporters, and tight junction proteins present barriers to material translocation across the olfactory epithelium. Uptake of nanoparticles through the olfactory mucosa and translocation to the brain can be intracellular via cranial nerves (intraneuronal) or other cells of the olfactory epithelium, or extracellular along cranial nerve pathways (perineural) and surrounding blood vessels (perivascular, the glymphatic system). Transport rates vary greatly among the nose to brain pathways. Nanomedicine physicochemical properties (size, surface charge, surface coating, and particle stability) can affect uptake efficiency, which is usually less than 5%. Incorporation of therapeutic agents in nanoparticles has been shown to produce pharmacokinetic and pharmacodynamic benefits. Assessment of adverse effects has included olfactory mucosa toxicity, ciliotoxicity, and olfactory bulb and brain neurotoxicity. The results have generally suggested the investigated nanomedicines do not present significant toxicity. Research needs to advance the understanding of nanomedicine translocation and its drug cargo after intranasal administration is presented.<\/jats:p>\n                  <jats:p>\n                    This article is categorized under:\n                    <jats:list list-type=\"simple\">\n                      <jats:list-item>\n                        <jats:p>Therapeutic Approaches and Drug Discovery &gt; Nanomedicine for Neurological Disease<\/jats:p>\n                      <\/jats:list-item>\n                      <jats:list-item>\n                        <jats:p>Therapeutic Approaches and Drug Discovery &gt; Emerging Technologies<\/jats:p>\n                      <\/jats:list-item>\n                      <jats:list-item>\n                        <jats:p>Toxicology and Regulatory Issues in Nanomedicine &gt; Toxicology of Nanomaterials<\/jats:p>\n                      <\/jats:list-item>\n                    <\/jats:list>\n                  <\/jats:p>","DOI":"10.1002\/wnan.1767","type":"journal-article","created":{"date-parts":[[2021,12,27]],"date-time":"2021-12-27T01:00:41Z","timestamp":1640566841000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":43,"title":["Direct nose to the brain nanomedicine delivery presents a formidable challenge"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5188-3972","authenticated-orcid":false,"given":"Robert A.","family":"Yokel","sequence":"first","affiliation":[{"name":"Pharmaceutical Sciences, College of Pharmacy University of Kentucky  Lexington Kentucky USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,12,26]]},"reference":[{"key":"e_1_2_24_1_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2018.05.011"},{"key":"e_1_2_24_1_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2020.07.044"},{"key":"e_1_2_24_1_5_1","doi-asserted-by":"publisher","DOI":"10.2174\/0929867326666190827151741"},{"key":"e_1_2_24_1_6_1","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics12121230"},{"key":"e_1_2_24_1_7_1","doi-asserted-by":"publisher","DOI":"10.2174\/1381612826666200311131658"},{"key":"e_1_2_24_1_8_1","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics11020084"},{"key":"e_1_2_24_1_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijpharm.2019.05.032"},{"key":"e_1_2_24_1_10_1","unstructured":"N. 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