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Glial cell dysfunction has been implicated in in Rett syndrome (RTT) both in patients and in mouse models of this disorder and can affect synaptogenesis, glial metabolism and inflammation. Here we assessed whether treatment of adult (5\u20136\u2009months old) symptomatic <jats:italic>Mecp2<\/jats:italic>\u2010heterozygous female mice with <jats:italic>N<\/jats:italic>\u2010acetyl cysteine conjugated to dendrimer (D\u2010NAC), which is known to target glia and modulate inflammation and oxidative injury, results in improved behavioral phenotype, sleep and glial inflammatory profile. We show that unbiased global metabolomic analysis of the hippocampus and striatum in adult <jats:italic>Mecp2<\/jats:italic>\u2010heterozygous mice demonstrates significant differences in lipid metabolism associated with neuroinflammation, providing the rationale for targeting glial inflammation in this model. Our results demonstrate that treatment with D\u2010NAC (10\u2009mg\/kg NAC) once weekly is more efficacious than equivalently dosed free NAC in improving the gross neurobehavioral phenotype in symptomatic <jats:italic>Mecp2<\/jats:italic>\u2010heterozygous female mice. We also show that D\u2010NAC therapy is significantly better than saline in ameliorating several aspects of the abnormal phenotype including paw clench, mobility, fear memory, REM sleep and epileptiform activity burden. Systemic D\u2010NAC significantly improves microglial proinflammatory cytokine production and is associated with improvements in several aspects of the phenotype including paw clench, mobility, fear memory, and REM sleep, and epileptiform activity burden in comparison to saline\u2010treated <jats:italic>Mecp2<\/jats:italic>\u2010hetereozygous mice. Systemic glial\u2010targeted delivery of D\u2010NAC <jats:italic>after symptom onset<\/jats:italic> in an older clinically relevant Rett syndrome model shows promise in improving neurobehavioral impairments along with sleep pattern and epileptiform activity burden. These findings argue for the translational value of this approach for treatment of patients with Rett Syndrome.<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc15960-fig-0008-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p>","DOI":"10.1111\/jnc.15960","type":"journal-article","created":{"date-parts":[[2023,10,1]],"date-time":"2023-10-01T01:55:05Z","timestamp":1696125305000},"page":"841-854","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Dendrimer nanotherapy targeting of glial dysfunction improves inflammation and neurobehavioral phenotype in adult female <i>Mecp2<\/i>\u2010heterozygous mouse model of Rett syndrome"],"prefix":"10.1111","volume":"168","author":[{"given":"Elizabeth Smith","family":"Khoury","sequence":"first","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine Johns Hopkins University School of Medicine  Baltimore Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruchit V.","family":"Patel","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine Johns Hopkins University School of Medicine  Baltimore Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Caroline","family":"O'Ferrall","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine Johns Hopkins University School of Medicine  Baltimore Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amanda","family":"Fowler","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine Johns Hopkins University School of Medicine  Baltimore Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9895-6091","authenticated-orcid":false,"given":"Nirnath","family":"Sah","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine Johns Hopkins University School of Medicine  Baltimore Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anjali","family":"Sharma","sequence":"additional","affiliation":[{"name":"Center for Nanomedicine, Department of Ophthalmology, Wilmer Eye Institute Johns Hopkins University School of Medicine  Baltimore Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Siddharth","family":"Gupta","sequence":"additional","affiliation":[{"name":"Kennedy Krieger Institute  Baltimore Maryland USA"},{"name":"Department of Neurology Johns Hopkins University School of Medicine  Baltimore Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1229-8778","authenticated-orcid":false,"given":"Susanna","family":"Scafidi","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine Johns Hopkins University School of Medicine  Baltimore Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joshua S.","family":"Kurtz","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine Johns Hopkins University School of Medicine  Baltimore Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah J.","family":"Olmstead","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine Johns Hopkins University School of Medicine  Baltimore Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sapna R.","family":"Kudchadkar","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine Johns Hopkins University School of Medicine  Baltimore Maryland USA"},{"name":"Departments of Pediatrics and Physical Medicine and Rehabilitation Johns Hopkins University School of Medicine  Baltimore Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rangaramanujam M.","family":"Kannan","sequence":"additional","affiliation":[{"name":"Center for Nanomedicine, Department of Ophthalmology, Wilmer Eye Institute Johns Hopkins University School of Medicine  Baltimore Maryland USA"},{"name":"Departments of Chemical and Biomolecular Engineering, and Materials Science and Engineering Johns Hopkins University  Baltimore Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mary E.","family":"Blue","sequence":"additional","affiliation":[{"name":"Department of Neurology Johns Hopkins University School of Medicine  Baltimore Maryland USA"},{"name":"Department of Neuroscience Johns Hopkins University School of Medicine  Baltimore Maryland USA"},{"name":"Hugo W. 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