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Despite promise, clinical translation of neuronanomedicine remains elusive, possibly due to a dearth of information regarding the effect of the protein corona on these neuronanomedicines. The protein corona, a layer of proteins adsorbed to nanoparticles following exposure to biological fluids, ultimately determines the fate of nanoparticles in biological systems, dictating nanoparticle\u2013cell interactions. To date, few studies have investigated the effect of the protein corona on interactions with brain-derived cells, an important consideration for the development of neuronanomedicines. Here, two polymeric nanoparticles, poly(lactic-co-glycolic acid) (PLGA) and PLGA-polyethylene glycol (PLGA-PEG), were used to obtain serum-derived protein coronas. Protein corona characterization and liquid chromatography mass spectrometry analysis revealed distinct differences in biophysical properties and protein composition. PLGA protein coronas contained high abundance of globins (60%) and apolipoproteins (21%), while PLGA-PEG protein coronas contained fewer globins (42%) and high abundance of protease inhibitors (28%). Corona coated PLGA nanoparticles were readily internalized into microglia and neuronal cells, but not into astrocytes. Internalization of nanoparticles was associated with pro-inflammatory cytokine release and decreased neuronal cell viability, however, viability was rescued in cells treated with corona coated nanoparticles. These results showcase the importance of the protein corona in mediating nanoparticle\u2013cell interactions.<\/jats:p>","DOI":"10.1088\/1361-6528\/ad7b40","type":"journal-article","created":{"date-parts":[[2024,9,19]],"date-time":"2024-09-19T12:41:00Z","timestamp":1726749660000},"page":"495101","update-policy":"https:\/\/doi.org\/10.1088\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Serum-derived protein coronas affect nanoparticle interactions with brain cells"],"prefix":"10.1088","volume":"35","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6398-616X","authenticated-orcid":true,"given":"Nabila","family":"Morshed","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4533-6627","authenticated-orcid":true,"given":"Claire","family":"Rennie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9413-0978","authenticated-orcid":false,"given":"Wei","family":"Deng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4380-7600","authenticated-orcid":true,"given":"Lyndsey","family":"Collins-Praino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0035-7961","authenticated-orcid":true,"given":"Andrew","family":"Care","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"266","published-online":{"date-parts":[[2024,9,25]]},"reference":[{"key":"nanoad7b40bib1","doi-asserted-by":"publisher","first-page":"631","DOI":"10.1016\/j.bbi.2023.11.004","volume":"115","author":"Boyton","year":"2024","journal-title":"Brain Behav. 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