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Nevertheless, despite the promising results observed, there has been a growing interest in the use of cell-free therapies in regenerative medicine, such as the use of stem cell secretome. This review provides an in-depth compilation of data regarding the secretome composition, protocols used for its preparation, as well as existing information on the impact of secretome administration on various brain conditions, pointing out gaps and highlighting relevant findings. Moreover, due to the ability of MSCs to respond differently depending on their microenvironment, preconditioning of MSCs has been used to modulate their composition and, consequently, their therapeutic potential. The different strategies used to modulate the MSC secretome were also reviewed. Although secretome administration was effective in improving functional impairments, regeneration, neuroprotection, and reducing inflammation in brain tissue, a high variability in secretome preparation and administration was identified, compromising the transposition of preclinical data to clinical studies. Indeed, there are no reports of the use of secretome in clinical trials. Despite the existing limitations and lack of clinical data, secretome administration is a potential tool for the treatment of various diseases that impact the CNS.<\/jats:p>","DOI":"10.3390\/ijms242216544","type":"journal-article","created":{"date-parts":[[2023,11,20]],"date-time":"2023-11-20T10:32:32Z","timestamp":1700476352000},"page":"16544","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Secretome as a Tool to Treat Neurological Conditions: Are We Ready?"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5490-5759","authenticated-orcid":false,"given":"Andreia Valente","family":"da Silva","sequence":"first","affiliation":[{"name":"Health Sciences Research Center (CICS-UBI), University of Beira Interior, 6201-506 Covilh\u00e3, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3951-1599","authenticated-orcid":false,"given":"In\u00eas","family":"Serrenho","sequence":"additional","affiliation":[{"name":"Health Sciences Research Center (CICS-UBI), University of Beira Interior, 6201-506 Covilh\u00e3, Portugal"},{"name":"Center for Neuroscience and Cell Biology (CNC-UC), University of Coimbra, 3004-504 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2181-2203","authenticated-orcid":false,"given":"Beatriz","family":"Ara\u00fajo","sequence":"additional","affiliation":[{"name":"Health Sciences Research Center (CICS-UBI), University of Beira Interior, 6201-506 Covilh\u00e3, Portugal"}]},{"given":"Alexandre Martins","family":"Carvalho","sequence":"additional","affiliation":[{"name":"Health Sciences Research Center (CICS-UBI), University of Beira Interior, 6201-506 Covilh\u00e3, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7942-0432","authenticated-orcid":false,"given":"Gra\u00e7a","family":"Baltazar","sequence":"additional","affiliation":[{"name":"Health Sciences Research Center (CICS-UBI), University of Beira Interior, 6201-506 Covilh\u00e3, Portugal"},{"name":"Faculty of Health Sciences, University of Beira Interior, 6201-506 Covilh\u00e3, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Fu, X., Liu, G., Halim, A., Ju, Y., Luo, Q., and Song, A.G. 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