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Yet how such coatings influence protein corona formation and hemocompatibility in human blood remains poorly understood. To address this, we precoated model hydrophilic and hydrophobic polystyrene NPs with either fatted or defatted human serum albumin (HSA) and exposed them to human plasma and blood-based models. Proteomic analysis of the adsorbed protein corona revealed formulation-dependent differences in composition, but an overall favorable profile characterized by enrichment of dysopsonins (HSA and apolipoproteins) and depletion of major opsonins (complement proteins and immunoglobulins). Consistent with these findings, NP uptake by phagocytic blood cells was low across all formulations. However, evaluation in physiologically relevant human-derived models uncovered formulation-dependent biological responses. Specifically, three of the four HSA-precoated NPs exhibited complement activation or prothrombotic tendencies, whereas fatted HSA on hydrophobic NPs showed consistent blood compatibility across multiple assays. Taken together, these findings demonstrate that the hemocompatibility of albumin-coated NPs is determined by the interplay between NP core surface chemistry and albumin formulation, rather than by albumin precoating alone, providing important design criteria for albumin-based NP coatings.<\/jats:p>","DOI":"10.1021\/acsomega.6c04297","type":"journal-article","created":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T08:01:45Z","timestamp":1786953705000},"page":"51281-51295","source":"Crossref","is-referenced-by-count":1,"title":["Albumin Precoating of Nanoparticles: A Reliable Stealth\nStrategy?"],"prefix":"10.1021","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3303-1431","authenticated-orcid":true,"given":"Vinicius S.","family":"Guido","sequence":"first","affiliation":[{"name":"Federal University of Sa\u0303o Paulo (UNIFESP) , , , ,","place":["Sa\u0303o Paulo, Sa\u0303o Paulo, Brazil, 04044-020"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andre\u0301 F.","family":"Lima","sequence":"additional","affiliation":[{"name":"Federal University of Sa\u0303o Paulo (UNIFESP) , , , ,","place":["Sa\u0303o Paulo, Sa\u0303o Paulo, Brazil, 04044-020"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natasha","family":"Mina","sequence":"additional","affiliation":[{"name":"Federal University of Sa\u0303o Paulo (UNIFESP) , , , ,","place":["Sa\u0303o Paulo, Sa\u0303o Paulo, Brazil, 04044-020"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jackelinne Y.","family":"Hayashi","sequence":"additional","affiliation":[{"name":"Federal University of Sa\u0303o Paulo (UNIFESP) , , , ,","place":["Sa\u0303o Paulo, Sa\u0303o Paulo, Brazil, 04044-020"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ismael F.","family":"Lima","sequence":"additional","affiliation":[{"name":"Butantan Institute , , , ,","place":["Sa\u0303o Paulo, Sa\u0303o Paulo, Brazil, 05503-900"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leo K.","family":"Iwai","sequence":"additional","affiliation":[{"name":"Butantan Institute , , , ,","place":["Sa\u0303o Paulo, Sa\u0303o Paulo, Brazil, 05503-900"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Luiza V.","family":"Oliva","sequence":"additional","affiliation":[{"name":"Federal University of Sa\u0303o Paulo (UNIFESP) , , , ,","place":["Sa\u0303o Paulo, Sa\u0303o Paulo, Brazil, 04044-020"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernando L. A.","family":"Fonseca","sequence":"additional","affiliation":[{"name":"Federal University of Sa\u0303o Paulo (UNIFESP) , , , ,","place":["Diadema, Sa\u0303o Paulo, Brazil, 09913-030"]},{"name":"Faculty of Medicine of ABC (FMABC) , , , ,","place":["Santo Andre, Sa\u0303o Paulo, Brazil, 09060-650"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1332-8895","authenticated-orcid":true,"given":"Alexandre K.","family":"Tashima","sequence":"additional","affiliation":[{"name":"Federal University of Sa\u0303o Paulo (UNIFESP) , , , ,","place":["Sa\u0303o Paulo, Sa\u0303o Paulo, Brazil, 04044-020"]},{"name":"Federal University of Sa\u0303o Paulo (UNIFESP) , , , ,","place":["Sa\u0303o Paulo, Sa\u0303o Paulo, Brazil, 04039-032"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7443-5363","authenticated-orcid":true,"given":"Alioscka A.","family":"Sousa","sequence":"additional","affiliation":[{"name":"Federal University of Sa\u0303o Paulo (UNIFESP) , , , ,","place":["Sa\u0303o Paulo, Sa\u0303o Paulo, Brazil, 04044-020"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,17]]},"reference":[{"key":"2026090307182521100_cit1","doi-asserted-by":"publisher","first-page":"114635","DOI":"10.1016\/j.addr.2022.114635","article-title":"Protein corona: Friend\nor foe? Co-opting serum proteins for nanoparticle\ndelivery","volume":"192","author":"Kim","year":"2023","journal-title":"Adv. Drug Delivery Rev."},{"key":"2026090307182521100_cit2","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1016\/j.actbio.2021.05.019","article-title":"The protein corona and its effects\non nanoparticle-based drug delivery systems","volume":"129","author":"Li","year":"2021","journal-title":"Acta Biomater."},{"issue":"1","key":"2026090307182521100_cit3","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1146\/annurev-pharmtox-032320-110338","article-title":"Nanoparticle toxicology","volume":"61","author":"Yang","year":"2021","journal-title":"Annu.\nRev. Pharmacol. Toxicol."},{"issue":"3","key":"2026090307182521100_cit4","doi-asserted-by":"publisher","first-page":"1031","DOI":"10.1007\/s00204-016-1797-5","article-title":"Protein bio-corona:\ncritical issue in immune nanotoxicology","volume":"91","author":"Neagu","year":"2017","journal-title":"Arch.\nToxicol."},{"issue":"1","key":"2026090307182521100_cit5","doi-asserted-by":"publisher","first-page":"715","DOI":"10.1007\/s12274-022-4849-6","article-title":"The Yin and\nYang of the protein corona on the delivery journey of nanoparticles","volume":"16","author":"Wang","year":"2023","journal-title":"Nano Res."},{"issue":"4","key":"2026090307182521100_cit6","doi-asserted-by":"publisher","DOI":"10.1002\/wnan.1615","article-title":"Impact of\nthe protein corona on nanomaterial immune response and targeting ability","volume":"12","author":"Digiacomo","year":"2020","journal-title":"Wiley Interdiscip. Rev.: Nanomed. Nanobiotechnol."},{"issue":"14","key":"2026090307182521100_cit7","doi-asserted-by":"publisher","first-page":"2756","DOI":"10.1039\/C4CC07644C","article-title":"Nanoparticle\u2013blood\ninteractions: the implications on solid tumour targeting","volume":"51","author":"Lazarovits","year":"2015","journal-title":"Chem. Commun."},{"key":"2026090307182521100_cit8","doi-asserted-by":"publisher","first-page":"1101387","DOI":"10.3389\/fimmu.2023.1101387","article-title":"In vitro evaluation\nof iron oxide nanoparticle-induced thromboinflammatory response using\na combined human whole blood and endothelial cell model","volume":"14","author":"Gerogianni","year":"2023","journal-title":"Front. Immunol."},{"issue":"6","key":"2026090307182521100_cit9","doi-asserted-by":"publisher","first-page":"969","DOI":"10.2217\/nnm.13.49","article-title":"Nanoparticles\nand the blood coagulation system. 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Chem.\nB"},{"issue":"1","key":"2026090307182521100_cit22","doi-asserted-by":"publisher","first-page":"4548","DOI":"10.1038\/s41467-018-06979-4","article-title":"Cloaking nanoparticles with protein corona shield for\ntargeted drug delivery","volume":"9","author":"Oh","year":"2018","journal-title":"Nat. Commun."},{"issue":"9","key":"2026090307182521100_cit23","doi-asserted-by":"publisher","first-page":"11950","DOI":"10.1021\/acsnano.0c05097","article-title":"Cloaking\nsilica nanoparticles with\nfunctional protein coatings for reduced complement activation and\ncellular uptake","volume":"14","author":"Park","year":"2020","journal-title":"ACS Nano"},{"issue":"1","key":"2026090307182521100_cit24","doi-asserted-by":"publisher","first-page":"3686","DOI":"10.1038\/s41467-019-11642-7","article-title":"Interplay of protein\ncorona and immune cells controls blood residency of liposomes","volume":"10","author":"Giulimondi","year":"2019","journal-title":"Nat. Commun"},{"issue":"22","key":"2026090307182521100_cit25","doi-asserted-by":"publisher","first-page":"10731","DOI":"10.1039\/C8NR03331E","article-title":"Exploiting\nthe biomolecular corona: pre-coating of nanoparticles enables controlled\ncellular interactions","volume":"10","author":"Simon","year":"2018","journal-title":"Nanoscale"},{"issue":"1","key":"2026090307182521100_cit26","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1186\/s12951-025-03565-x","article-title":"Engineered\nprotein corona sustains stealth functionality of nanocarriers in plasma","volume":"23","author":"Zhang","year":"2025","journal-title":"J. Nanobiotechnol."},{"key":"2026090307182521100_cit27","doi-asserted-by":"publisher","first-page":"13267","DOI":"10.2147\/IJN.S476241","article-title":"Stealth-engineered\nalbumin-coated nanoparticles for targeted therapy: effective drug\ndelivery and tumor suppression in xenograft-zebrafish model","volume":"Volume 19","author":"Bozzer","year":"2024","journal-title":"Int. J. Nanomed."},{"issue":"40","key":"2026090307182521100_cit28","doi-asserted-by":"publisher","DOI":"10.1002\/slct.202401823","article-title":"Application of albumin\nin nanodrugs for cancer therapy","volume":"9","author":"Li","year":"2024","journal-title":"ChemistrySelect"},{"issue":"8","key":"2026090307182521100_cit29","doi-asserted-by":"publisher","first-page":"2668","DOI":"10.3109\/10717544.2015.1048488","article-title":"Albumin\ncorona on nanoparticles\u2013a\nstrategic approach in drug delivery","volume":"23","author":"Mariam","year":"2016","journal-title":"Drug Delivery"},{"issue":"7","key":"2026090307182521100_cit30","doi-asserted-by":"publisher","first-page":"3084","DOI":"10.1021\/acsabm.9b00386","article-title":"Insights into preformed\nhuman serum albumin corona on iron oxide nanoparticles: structure,\neffect of particle size, impact on MRI efficiency, and metabolization","volume":"2","author":"Moya","year":"2019","journal-title":"ACS Appl. Bio Mater."},{"issue":"33","key":"2026090307182521100_cit31","doi-asserted-by":"publisher","first-page":"8521","DOI":"10.1016\/j.biomaterials.2013.07.102","article-title":"Preformed albumin\ncorona, a protective coating for\nnanoparticles based drug delivery system","volume":"34","author":"Peng","year":"2013","journal-title":"Biomaterials"},{"issue":"6","key":"2026090307182521100_cit32","doi-asserted-by":"publisher","first-page":"2324","DOI":"10.1021\/acs.langmuir.7b04024","article-title":"Ligand-mediated coating of liposomes\nwith human serum albumin","volume":"34","author":"Sato","year":"2018","journal-title":"Langmuir"},{"issue":"10","key":"2026090307182521100_cit33","doi-asserted-by":"publisher","first-page":"3455","DOI":"10.1016\/j.biomaterials.2013.12.100","article-title":"Blood protein coating of gold nanoparticles\nas potential tool for organ targeting","volume":"35","author":"Scha\u0308ffler","year":"2014","journal-title":"Biomaterials"},{"key":"2026090307182521100_cit34","doi-asserted-by":"publisher","first-page":"206","DOI":"10.1016\/j.biomaterials.2018.07.024","article-title":"Surface modification\nof polymer nanoparticles with\nnative albumin for enhancing drug delivery to solid tumors","volume":"180","author":"Hyun","year":"2018","journal-title":"Biomaterials"},{"issue":"2","key":"2026090307182521100_cit35","doi-asserted-by":"publisher","first-page":"205","DOI":"10.2217\/nnm.14.86","article-title":"Enhanced\nbiostability of nanoparticle-based drug delivery systems by albumin\ncorona","volume":"10","author":"Peng","year":"2015","journal-title":"Nanomedicine"},{"issue":"1","key":"2026090307182521100_cit36","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1038\/s42003-020-0817-4","article-title":"pH-responsive high\nstability polymeric nanoparticles for targeted delivery of anticancer\ntherapeutics","volume":"3","author":"Palanikumar","year":"2020","journal-title":"Comm. Biol."},{"key":"2026090307182521100_cit37","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1016\/j.addr.2018.07.011","article-title":"Harnessing albumin as a carrier for\ncancer therapies","volume":"130","author":"Hoogenboezem","year":"2018","journal-title":"Adv. Drug Delivery Rev."},{"issue":"5","key":"2026090307182521100_cit38","doi-asserted-by":"publisher","first-page":"1862","DOI":"10.1021\/acs.molpharmaceut.1c00046","article-title":"The uniqueness\nof albumin as a carrier in nanodrug delivery","volume":"18","author":"Spada","year":"2021","journal-title":"Mol. Pharmaceutics"},{"issue":"4","key":"2026090307182521100_cit39","doi-asserted-by":"publisher","first-page":"3357","DOI":"10.1021\/nn405830g","article-title":"Cryptic epitopes\nof albumin determine mononuclear phagocyte\nsystem clearance of nanomaterials","volume":"8","author":"Mortimer","year":"2014","journal-title":"ACS Nano"},{"issue":"1","key":"2026090307182521100_cit40","doi-asserted-by":"publisher","first-page":"648","DOI":"10.1038\/s41467-020-20886-7","article-title":"Surface chemistry-mediated\nmodulation of adsorbed albumin folding state specifies nanocarrier\nclearance by distinct macrophage subsets","volume":"12","author":"Vincent","year":"2021","journal-title":"Nat.\nCommun."},{"issue":"6","key":"2026090307182521100_cit41","doi-asserted-by":"publisher","first-page":"2978","DOI":"10.1021\/acs.molpharmaceut.3c00021","article-title":"Effect of\nalbumin corona conformation on in vitro and in vivo profiles\nof intravenously administered nanoparticles","volume":"20","author":"Wu","year":"2023","journal-title":"Mol. 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Phys."},{"issue":"1","key":"2026090307182521100_cit45","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1016\/0005-2795(78)90548-2","article-title":"Influence\nof fatty acid and time\nof focusing on the isoelectric focusing of human plasma albumin","volume":"533","author":"Basu","year":"1978","journal-title":"Biochim. Biophys. Acta, Protein Struct."},{"key":"2026090307182521100_cit46","doi-asserted-by":"publisher","first-page":"548","DOI":"10.1016\/j.jconrel.2021.08.048","article-title":"Complement\nopsonization of nanoparticles: Differences between humans and preclinical\nspecies","volume":"338","author":"Li","year":"2021","journal-title":"J. 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Mater."},{"issue":"12","key":"2026090307182521100_cit49","doi-asserted-by":"publisher","first-page":"1028","DOI":"10.3390\/nano8121028","article-title":"Surface\ncharge-dependent cellular\nuptake of polystyrene nanoparticles","volume":"8","author":"Jeon","year":"2018","journal-title":"Nanomaterials"},{"issue":"2","key":"2026090307182521100_cit50","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1016\/j.nano.2008.02.002","article-title":"Polystyrene\nnanoparticle\ntrafficking across alveolar epithelium","volume":"4","author":"Yacobi","year":"2008","journal-title":"Nanomed.:\nNanotechnol. Biol. 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