{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T09:03:04Z","timestamp":1789722184448,"version":"4.0.1"},"reference-count":76,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T00:00:00Z","timestamp":1789430400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T00:00:00Z","timestamp":1789430400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Small"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Lipid nanoparticles (LNPs) preferentially accumulate in the liver, but hepatic tropism alone does not ensure productive RNA interference. Here, we screened a library of LNPs in which lipid composition was varied to generate distinct protein corona identities and identify formulations capable of combining liver accumulation with functional siRNA delivery. LNP1 emerged as the lead formulation, showing favorable physicochemical properties, high transfection efficiency, and enhanced hepatic accumulation. Proteomic analysis associated this behavior with a distinct multicomponent corona signature. When loaded with siRNA targeting tissue inhibitor of metalloproteinases 1 (TIMP1), a key regulator of extracellular matrix turnover and fibrosis, LNP1 was efficiently internalized by primary Kupffer cells (KCs) and induced robust target knockdown. Consistent with this cellular preference, quartz crystal microbalance measurements showed that corona formation increased LNP1 binding to MARCO, a scavenger receptor expressed by KCs. In a mouse model of primary biliary cholangitis, repeated administration of siTIMP1\u2010loaded LNP1 reduced TIMP1 expression in KCs, reactivated extracellular\u2010matrix\u2010degradative pathways, suppressed pro\u2010inflammatory signaling and macrophage infiltration, alleviated cholestasis and attenuated liver fibrosis. These findings connect systematic variation in lipid composition with corona identity, hepatic tropism, and functional gene silencing, supporting protein corona engineering as a strategy to bridge liver accumulation with productive siRNA delivery.<\/jats:p>","DOI":"10.1002\/smll.75537","type":"journal-article","created":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T10:54:44Z","timestamp":1789469684000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Protein Corona Engineering of Lipid Nanoparticles Enables Efficient Functional Gene Silencing in the Liver"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1910-0872","authenticated-orcid":false,"given":"Naths G.","family":"Sukubo","sequence":"first","affiliation":[{"name":"School of Medicine and Surgery University of Milano\u2010Bicocca  Monza Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8206-8994","authenticated-orcid":false,"given":"Serena","family":"Renzi","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine Sapienza University of Rome  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9016-410X","authenticated-orcid":false,"given":"Martina B.","family":"Violatto","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Pharmacology Istituto di Ricerche Farmacologiche \u201cMario Negri\u201d IRCCS  Milano Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leila","family":"Altigieri","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Pharmacology Istituto di Ricerche Farmacologiche \u201cMario Negri\u201d IRCCS  Milano Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1017-9625","authenticated-orcid":false,"given":"Anna L.","family":"Capriotti","sequence":"additional","affiliation":[{"name":"Department of Chemistry Sapienza University of Rome  Rome Italy"},{"name":"Interuniversity Consortium INBB \u2013 Biostructures and Biosystems National Institute  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Cerrato","sequence":"additional","affiliation":[{"name":"Department of Chemistry Sapienza University of Rome  Rome Italy"},{"name":"Interuniversity Consortium INBB \u2013 Biostructures and Biosystems National Institute  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aldo","family":"Lagan\u00e0","sequence":"additional","affiliation":[{"name":"Department of Chemistry Sapienza University of Rome  Rome Italy"},{"name":"Interuniversity Consortium INBB \u2013 Biostructures and Biosystems National Institute  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3362-7160","authenticated-orcid":false,"given":"Luca","family":"Digiacomo","sequence":"additional","affiliation":[{"name":"Department of Medical Surgical Sciences and Biotechnologies Sapienza University of Rome  Latina Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9626-315X","authenticated-orcid":false,"given":"Erica","family":"Quagliarini","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine Sapienza University of Rome  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5690-0604","authenticated-orcid":false,"given":"Antonio","family":"Minopoli","sequence":"additional","affiliation":[{"name":"Department of Neuroscience Catholic University of Sacred Heart  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0029-1309","authenticated-orcid":false,"given":"Massimiliano","family":"Papi","sequence":"additional","affiliation":[{"name":"Department of Neuroscience Catholic University of Sacred Heart  Rome Italy"},{"name":"Fondazione Policlinico Universitario A. Gemelli IRCCS  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6158-5880","authenticated-orcid":false,"given":"Daniela","family":"Pozzi","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine Sapienza University of Rome  Rome Italy"},{"name":"Center for Nanotechnology Applied to Engineering (CNIS) Sapienza University of Rome  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7451-0271","authenticated-orcid":false,"given":"Carlo A.","family":"Scir\u00e8","sequence":"additional","affiliation":[{"name":"School of Medicine and Surgery University of Milano\u2010Bicocca  Monza Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3262-1998","authenticated-orcid":false,"given":"Pietro","family":"Invernizzi","sequence":"additional","affiliation":[{"name":"School of Medicine and Surgery University of Milano\u2010Bicocca  Monza Italy"},{"name":"Division of Gastroenterology Center for Autoimmune Liver Diseases European Reference Network on Hepatological Diseases (ERN RARE\u2010LIVER) IRCCS Fondazione San Gerardo Dei Tintori  Monza Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0239-9532","authenticated-orcid":false,"given":"Paolo","family":"Bigini","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Pharmacology Istituto di Ricerche Farmacologiche \u201cMario Negri\u201d IRCCS  Milano Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8636-4475","authenticated-orcid":false,"given":"Giulio","family":"Caracciolo","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine Sapienza University of Rome  Rome Italy"},{"name":"Center for Nanotechnology Applied to Engineering (CNIS) Sapienza University of Rome  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,15]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41565\u2010019\u20100591\u2010y"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41578\u2010021\u201000358\u20100"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1039\/D5NH00351B"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201203263"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1021\/mp400584h"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nnano.2012.207"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja107583h"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1021\/la202912f"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nano.2014.11.003"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/nnano.2012.237"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1039\/C8NR03331E"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2024.05.003"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1039\/C4RA13335H"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41565\u2010020\u20100669\u20106"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41565\u2010023\u201001455\u20107"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcancer.2010.05.002"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2010.01.003"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24021641"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2014.02.003"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.28641"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2026.119770"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1039\/C1CS15233E"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamem.2015.11.012"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010024\u201053569\u20108"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/nnano.2015.47"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1039\/C5NR01970B"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsnano.6b07933"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni.1923"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/nnano.2016.269"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0163\u20107827(03)00033\u2010X"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics14122605"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1039\/D2NR01878K"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.471060"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1513\/AnnalsATS.201507\u2010468KV"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/0168\u20103659(95)00167\u20100"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.vascn.2004.08.014"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.addr.2022.114635"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1039\/C7NR06437C"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI118883"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI25327"},{"key":"e_1_2_10_42_1","volume-title":"Physiology, Albumin","author":"Moman R. N.","year":"2026"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1357\u20102725(99)00005\u20109"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1021\/am404171h"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtm.2025.101436"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2017.01.039"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12951\u2010021\u201001097\u20108"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.1021\/acschemneuro.3c00728"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.1002\/adhm.202505261"},{"key":"e_1_2_10_50_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010018\u201006318\u20107"},{"key":"e_1_2_10_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2019.08.017"},{"key":"e_1_2_10_52_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfaf037"},{"key":"e_1_2_10_53_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacsau.3c00084"},{"key":"e_1_2_10_54_1","doi-asserted-by":"publisher","DOI":"10.1038\/labinvest.2016.116"},{"key":"e_1_2_10_55_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010019\u201009234\u20106"},{"issue":"7","key":"e_1_2_10_56_1","first-page":"634","article-title":"Timp\u20101 Promotes Expression of Mcp\u20101 and Macrophage Migration by Inducing Fli\u20101 in Experimental Liver Fibrosis","volume":"12","author":"Huang X.","year":"2024","journal-title":"Journal of Clinical and Translational Hepatology"},{"key":"e_1_2_10_57_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cimid.2009.07.001"},{"key":"e_1_2_10_58_1","doi-asserted-by":"publisher","DOI":"10.3762\/bjnano.16.10"},{"key":"e_1_2_10_59_1","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.25589"},{"key":"e_1_2_10_60_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00699.2023"},{"key":"e_1_2_10_61_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2023.08.001"},{"key":"e_1_2_10_62_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvu072"},{"key":"e_1_2_10_63_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.matbio.2015.03.005"},{"key":"e_1_2_10_64_1","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics13081292"},{"key":"e_1_2_10_65_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23010146"},{"key":"e_1_2_10_66_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140\u20106736(24)01303\u20105"},{"key":"e_1_2_10_67_1","doi-asserted-by":"publisher","DOI":"10.4292\/wjgpt.v6.i3.32"},{"key":"e_1_2_10_68_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2011.02.031"},{"key":"e_1_2_10_69_1","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2017-315259"},{"key":"e_1_2_10_70_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1497026"},{"key":"e_1_2_10_71_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2010.03.008"},{"key":"e_1_2_10_72_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010024\u201067926\u20106"},{"key":"e_1_2_10_73_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells10102759"},{"key":"e_1_2_10_74_1","doi-asserted-by":"publisher","DOI":"10.1039\/C9LC00341J"},{"key":"e_1_2_10_75_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00216\u2010017\u20100822\u20108"},{"key":"e_1_2_10_76_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2016.136"},{"key":"e_1_2_10_77_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF01337937"}],"container-title":["Small"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/smll.75537","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/smll.75537","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/smll.75537","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T08:35:33Z","timestamp":1789720533000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/smll.75537"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,15]]},"references-count":76,"alternative-id":["10.1002\/smll.75537"],"URL":"https:\/\/doi.org\/10.1002\/smll.75537","archive":["Portico"],"relation":{},"ISSN":["1613-6810","1613-6829"],"issn-type":[{"value":"1613-6810","type":"print"},{"value":"1613-6829","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,15]]},"assertion":[{"value":"2026-01-20","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-20","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-15","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e75537"}}