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MPS I affects several tissues, including the brain, leading to cognitive impairment in the severe form of the disease. Currently available treatments do not reach the brain. Therefore, in this study, we performed nasal administration (NA) of liposomal complexes carrying two plasmids encoding for the CRISPR\/Cas9 system and for the <jats:italic>IDUA<\/jats:italic> gene targeting the <jats:italic>ROSA26<\/jats:italic> locus, aiming at brain delivery in MPS I mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Liposomes were prepared by microfluidization, and the plasmids were complexed to the formulations by adsorption. Physicochemical characterization of the formulations and complexes, in vitro permeation, and mucoadhesion in porcine nasal mucosa (PNM) were assessed. We performed NA repeatedly for 30\u2009days in young MPS I mice, which were euthanized at 6\u00a0months of age after performing behavioral tasks, and biochemical and molecular aspects were evaluated.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Monodisperse mucoadhesive complexes around 110\u2009nm, which are able to efficiently permeate the PNM. In animals, the treatment led to a modest increase in IDUA activity in the lung, heart, and brain areas, with reduction of glycosaminoglycan (GAG) levels in serum, urine, tissues, and brain cortex. Furthermore, treated mice showed improvement in behavioral tests, suggesting prevention of the cognitive damage.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Nonviral gene editing performed through nasal route represents a potential therapeutic alternative for the somatic and neurologic symptoms of MPS I and possibly for other neurological disorders.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jgm.3410","type":"journal-article","created":{"date-parts":[[2022,1,15]],"date-time":"2022-01-15T01:14:58Z","timestamp":1642209298000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Brain and visceral gene editing of mucopolysaccharidosis I mice by nasal delivery of the CRISPR\/Cas9 system"],"prefix":"10.1002","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7178-3853","authenticated-orcid":false,"given":"Luisa Natalia 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