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As fibrosis progresses, liver sinusoidal endothelial cells (LSECs) become defenestrated and restrict trans-sinusoidal exchange, thereby limiting drug access to hepatic stellate cells (HSCs) within the perisinusoidal space. Here, we developed a lipoprotein mimetic liposomal nanocarrier, SV@SRB-Lip, to exploit scavenger receptor class B type 1 (SR-B1)-associated transendothelial transport across capillarized LSECs and enhance downstream delivery toward HSC-associated fibrotic regions. SV@SRB-Lip was engineered as a simvastatin loaded liposomal platform incorporating an ApoA-I-mimetic SRB peptide, an MMP-responsive linker, and a vitamin A modified lipid moiety. SV@SRB-Lip promoted transport across the LSEC monolayer in vitro, and this effect was reduced by SR-B1 silencing, supporting the involvement of SR-B1-associated endothelial transport. In MASH mice, SV@SRB-Lip enhanced hepatic delivery and distributed toward HSC associated fibrotic regions. The MMP-responsive design increased the relative accessibility of vitamin A within the fibrotic microenvironment, supporting downstream HSC associated uptake. As a result, SV@SRB-Lip increased hepatic simvastatin accumulation, suppressed HSC activation and collagen deposition, and improved MASH associated fibrosis. These findings suggest that SR-B1-associated endothelial transport can be harnessed to overcome the capillarized sinusoidal barrier and improve antifibrotic nanomedicine delivery in MASH.<\/jats:p>","DOI":"10.1021\/acsnano.6c05500","type":"journal-article","created":{"date-parts":[[2026,9,13]],"date-time":"2026-09-13T15:01:20Z","timestamp":1789311680000},"page":"25335-25351","source":"Crossref","is-referenced-by-count":0,"title":["Scavenger Receptor\nClass B Type 1 Mediated Transport\nEnables Delivery Across Capillarized Liver Sinusoids in Metabolic\nDysfunction-Associated Steatohepatitis"],"prefix":"10.1021","volume":"20","author":[{"given":"Ruyan","family":"Yuan","sequence":"first","affiliation":[{"name":"Zhengzhou University , , ,","place":["Zhengzhou, China, 450001"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiamin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Zhengzhou University , , ,","place":["Zhengzhou, China, 450001"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yamei","family":"Huang","sequence":"additional","affiliation":[{"name":"Zhengzhou University , , ,","place":["Zhengzhou, China, 450001"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiyang","family":"Meng","sequence":"additional","affiliation":[{"name":"Zhengzhou University , , ,","place":["Zhengzhou, China, 450001"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siyan","family":"Liu","sequence":"additional","affiliation":[{"name":"Zhengzhou University , , ,","place":["Zhengzhou, China, 450001"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanqing","family":"Yang","sequence":"additional","affiliation":[{"name":"Zhengzhou University , , ,","place":["Zhengzhou, China, 450001"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinru","family":"Zhang","sequence":"additional","affiliation":[{"name":"Zhengzhou University , , , ,","place":["Zhengzhou, Henan, China, 450001"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengyu","family":"Yang","sequence":"additional","affiliation":[{"name":"Zhengzhou University , , ,","place":["Zhengzhou, China, 450001"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Menglei","family":"Liang","sequence":"additional","affiliation":[{"name":"Zhengzhou University , , ,","place":["Zhengzhou, China, 450001"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yipei","family":"Huang","sequence":"additional","affiliation":[{"name":"Zhengzhou University , , ,","place":["Zhengzhou, China, 450001"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang","family":"Liu","sequence":"additional","affiliation":[{"name":"National Center for Nanoscience and Technology , , ,","place":["Beijing, China, 100190"]},{"name":"University of Chinese Academy of Sciences , , ,","place":["Beijing, China, 100049"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaoxia","family":"Cheng","sequence":"additional","affiliation":[{"name":"National Center for Nanoscience and Technology , , ,","place":["Beijing, China, 100190"]},{"name":"University of Chinese Academy of Sciences , , ,","place":["Beijing, China, 100049"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaotian","family":"Li","sequence":"additional","affiliation":[{"name":"Zhengzhou University of Industrial Technology , , ,","place":["Zhengzhou, China, 451150"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cong","family":"Wang","sequence":"additional","affiliation":[{"name":"Zhengzhou University , , ,","place":["Zhengzhou, China, 450001"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jundong","family":"Yao","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology , , , ,","place":["Luoyang, Henan, China, 471003"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Zhengzhou University People\u2019s Hospital , , , ,","place":["Zhengzhou, Henan, China, 450003"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongdong","family":"Zhang","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology , , , ,","place":["Luoyang, Henan, China, 471003"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Zhao","sequence":"additional","affiliation":[{"name":"National Center for Nanoscience and Technology , , ,","place":["Beijing, China, 100190"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fenfen","family":"Li","sequence":"additional","affiliation":[{"name":"Zhengzhou University , , ,","place":["Zhengzhou, China, 450001"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2433-8842","authenticated-orcid":true,"given":"Lei","family":"Wang","sequence":"additional","affiliation":[{"name":"Zhengzhou University , , ,","place":["Zhengzhou, China, 450001"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,13]]},"reference":[{"issue":"10","key":"2026092216092271700_cit1","doi-asserted-by":"publisher","first-page":"633","DOI":"10.1038\/s41575-023-00807-x","article-title":"Hepatic inflammatory responses in liver fibrosis","volume":"20","author":"Hammerich","year":"2023","journal-title":"Nat. Rev. Gastroenterol. Hepatol"},{"issue":"5","key":"2026092216092271700_cit2","doi-asserted-by":"publisher","first-page":"70000","DOI":"10.1002\/EXP.70000","article-title":"Saikosaponin\nb1 Attenuates Liver Fibrosis by Blocking\nSTAT3\/Gli1 Interaction and Inducing Gli1 Degradation","volume":"5","author":"Shao","year":"2025","journal-title":"Exploration"},{"issue":"10","key":"2026092216092271700_cit3","doi-asserted-by":"publisher","first-page":"662","DOI":"10.1038\/s41575-023-00832-w","article-title":"Cellular stress in the pathogenesis\nof nonalcoholic steatohepatitis and liver fibrosis","volume":"20","author":"Sharma","year":"2023","journal-title":"Nat. Rev. Gastroenterol. Hepatol"},{"issue":"2","key":"2026092216092271700_cit4","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1016\/S2468-1253(23)00275-3","article-title":"Hepatocellular\nand extrahepatic cancer risk in people with non-alcoholic fatty liver\ndisease","volume":"9","author":"Thomas","year":"2024","journal-title":"Lancet Gastroenterol. Hepatol"},{"key":"2026092216092271700_cit5","doi-asserted-by":"publisher","first-page":"102641","DOI":"10.1016\/j.nantod.2025.102641","article-title":"Sono-mediated\nglutamine metabolic nanoplatform against liver fibrosis via breaking\nthe vicious self-injury of activated hepatic stellate cells","volume":"61","author":"Yang","year":"2025","journal-title":"Nano Today"},{"issue":"1","key":"2026092216092271700_cit6","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1038\/s41420-020-0252-9","article-title":"Atorvastatin-induced\nsenescence of hepatocellular carcinoma is mediated\nby downregulation of hTERT through the suppression of the IL-6\/STAT3\npathway","volume":"6","author":"Wang","year":"2020","journal-title":"Cell Death Discov"},{"issue":"1","key":"2026092216092271700_cit7","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1007\/s13273-019-0002-3","article-title":"Statin-induced liver\nand muscle toxicities","volume":"15","author":"Lee","year":"2019","journal-title":"Mol. 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Toxicol"},{"key":"2026092216092271700_cit8","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1016\/B978-0-323-95262-0.00014-0","article-title":"Liver fibrosis","volume-title":"Sinusoidal Cells\nIn Liver Diseases","author":"Chen","year":"2024"},{"issue":"4","key":"2026092216092271700_cit9","doi-asserted-by":"publisher","first-page":"1228","DOI":"10.1097\/HEP.0000000000001018","article-title":"Endothelial RUNX3 controls\nLSEC dysfunction and angiocrine LRG1 signaling\nto prevent liver fibrosis","volume":"81","author":"Ojha","year":"2025","journal-title":"Hepatology"},{"issue":"3","key":"2026092216092271700_cit10","doi-asserted-by":"publisher","first-page":"1259","DOI":"10.1002\/hep.30227","article-title":"Incomplete Differentiation\nof Engrafted Bone Marrow Endothelial Progenitor Cells Initiates Hepatic\nFibrosis in the Rat","volume":"69","author":"Maretti-Mira","year":"2019","journal-title":"Hepatology"},{"issue":"9","key":"2026092216092271700_cit11","doi-asserted-by":"publisher","first-page":"555","DOI":"10.1038\/s41575-018-0020-y","article-title":"Liver sinusoidal\nendothelial cells\u2500gatekeepers\nof hepatic immunity","volume":"15","author":"Shetty","year":"2018","journal-title":"Nat. Rev. Gastroenterol.\nHepatol"},{"issue":"2","key":"2026092216092271700_cit12","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1007\/s10456-025-09969-5","article-title":"The role\nof liver sinusoidal endothelial cells in metabolic dysfunction-associated\nsteatotic liver diseases and liver cancer: Mechanisms and potential\ntherapies","volume":"28","author":"Mo","year":"2025","journal-title":"Angiogenesis"},{"issue":"1","key":"2026092216092271700_cit13","doi-asserted-by":"publisher","first-page":"346","DOI":"10.1186\/s12964-024-01720-9","article-title":"Role of liver\nsinusoidal endothelial\ncell in metabolic dysfunction-associated fatty liver disease","volume":"22","author":"He","year":"2024","journal-title":"Cell Commun. Signal"},{"issue":"6","key":"2026092216092271700_cit14","doi-asserted-by":"publisher","first-page":"734","DOI":"10.1038\/s44161-024-00487-z","article-title":"Semaphorin-3A regulates\nliver sinusoidal endothelial cell porosity and promotes hepatic steatosis","volume":"3","author":"Eberhard","year":"2024","journal-title":"Nat. Cardiovasc. Res."},{"issue":"3","key":"2026092216092271700_cit15","doi-asserted-by":"publisher","first-page":"2803","DOI":"10.1007\/s11033-021-06269-1","article-title":"Liver sinusoidal endothelial cells\nare implicated in multiple fibrotic mechanisms","volume":"48","author":"Ma","year":"2021","journal-title":"Mol. Biol. Rep"},{"issue":"4","key":"2026092216092271700_cit16","doi-asserted-by":"publisher","first-page":"929","DOI":"10.3390\/cells9040929","article-title":"The Endothelium\nas a Driver of Liver Fibrosis and Regeneration","volume":"9","author":"Lafoz","year":"2020","journal-title":"Cells"},{"key":"2026092216092271700_cit17","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1002\/9781119436812.ch35","article-title":"Fenestrations\nin the Liver Sinusoidal Endothelial Cell","volume-title":"The\nLiver: Biology and Pathobiology","author":"Cogger","year":"2020"},{"issue":"17","key":"2026092216092271700_cit18","doi-asserted-by":"publisher","first-page":"2212206","DOI":"10.1002\/adma.202212206","article-title":"Restoration of Sinusoid Fenestrae Followed\nby Targeted Nanoassembly Delivery of an Anti-Fibrotic Agent Improves\nTreatment Efficacy in Liver Fibrosis","volume":"35","author":"Li","year":"2023","journal-title":"Adv. Mater."},{"key":"2026092216092271700_cit19","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1016\/j.ejpb.2018.11.018","article-title":"Prevention of hepatic\nstellate cell activation using JQ1- and atorvastatin-loaded chitosan\nnanoparticles as a promising approach in therapy of liver fibrosis","volume":"134","author":"Hassan","year":"2019","journal-title":"Eur. J. Pharm. Biopharm"},{"issue":"4","key":"2026092216092271700_cit20","doi-asserted-by":"publisher","first-page":"3910","DOI":"10.1021\/acsnano.8b06924","article-title":"Golgi Apparatus-Targeted\nChondroitin-Modified Nanomicelles Suppress Hepatic Stellate Cell Activation\nfor the Management of Liver Fibrosis","volume":"13","author":"Luo","year":"2019","journal-title":"ACS Nano"},{"issue":"1","key":"2026092216092271700_cit21","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1016\/j.ijpharm.2018.10.003","article-title":"Prevention of rat liver fibrosis by selective targeting\nof hepatic stellate cells using hesperidin carriers","volume":"552","author":"Morsy","year":"2018","journal-title":"Int. J. Pharm"},{"issue":"2","key":"2026092216092271700_cit22","doi-asserted-by":"publisher","first-page":"20240039","DOI":"10.1002\/EXP.20240039","article-title":"Engineered\nbrain-targeting exosome for reprogramming immunosuppressive microenvironment\nof glioblastoma","volume":"5","author":"Yang","year":"2024","journal-title":"Exploration"},{"issue":"7757","key":"2026092216092271700_cit23","doi-asserted-by":"publisher","first-page":"565","DOI":"10.1038\/s41586-019-1140-4","article-title":"SR-B1 drives endothelial cell LDL transcytosis\nvia DOCK4 to promote atherosclerosis","volume":"569","author":"Huang","year":"2019","journal-title":"Nature"},{"issue":"8\u20139","key":"2026092216092271700_cit24","doi-asserted-by":"publisher","first-page":"632","DOI":"10.1051\/medsci\/2019123","article-title":"SR-B1: An\nactive transporter of LDL through the endothelium","volume":"35","author":"Tedgui","year":"2019","journal-title":"Sciences"},{"key":"2026092216092271700_cit25","doi-asserted-by":"publisher","first-page":"5798","DOI":"10.1021\/ja069336k","article-title":"Ligand Conjugated Low-Density Lipoprotein\nNanoparticles for Enhanced\nOptical Cancer Imaging in Vivo","volume":"129","author":"Chen","year":"2007","journal-title":"J. Am. Chem.\nSoc"},{"issue":"3","key":"2026092216092271700_cit26","doi-asserted-by":"publisher","first-page":"430","DOI":"10.1002\/smll.200901515","article-title":"HDL-Mimicking Peptide\u2013Lipid\nNanoparticles with\nImproved Tumor Targeting","volume":"6","author":"Zhang","year":"2010","journal-title":"Small"},{"issue":"6","key":"2026092216092271700_cit27","doi-asserted-by":"publisher","first-page":"622","DOI":"10.1038\/s44161-024-00490-4","article-title":"Loss of fenestrae\nin liver sinusoidal\nendothelial cells contributes to MASLD","volume":"3","author":"Ciriaci","year":"2024","journal-title":"Nat.\nCardiovasc. Res"},{"issue":"1","key":"2026092216092271700_cit28","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1186\/s12860-020-00331-9","article-title":"Transcriptome\nand proteome profiling reveal complementary scavenger and immune features\nof rat liver sinusoidal endothelial cells and liver macrophages","volume":"21","author":"Bhandari","year":"2020","journal-title":"BMC Mol. Cell Biol"},{"issue":"7","key":"2026092216092271700_cit29","doi-asserted-by":"publisher","first-page":"481","DOI":"10.1038\/s41575-025-01068-6","article-title":"Hepatic stellate cells: Balancing\nhomeostasis, hepatoprotection\nand fibrogenesis in health and disease","volume":"22","author":"Schwabe","year":"2025","journal-title":"Nat.\nRev. Gastroenterol. Hepatol"},{"key":"2026092216092271700_cit30","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.adv2106","article-title":"Impaired TIM4- mediated\nefferocytosis by liver macrophages contributes to fibrosis in metabolic\ndysfunction\u2013associated steatohepatitis","volume":"17","author":"Shi","year":"2025","journal-title":"Sci. Transl. Med."},{"issue":"1\u20132","key":"2026092216092271700_cit31","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1007\/s00109-022-02282-4","article-title":"Recent updates on targeting the molecular\nmediators of NAFLD","volume":"101","author":"Wang","year":"2023","journal-title":"J. Mol. Med"},{"issue":"1","key":"2026092216092271700_cit32","doi-asserted-by":"publisher","first-page":"75","DOI":"10.3748\/wjg.v29.i1.75","article-title":"Emerging novel targets\nfor nonalcoholic fatty liver disease treatment: Evidence from recent\nbasic studies","volume":"29","author":"Wang","year":"2023","journal-title":"World J. Gastroenterol"},{"issue":"7","key":"2026092216092271700_cit33","doi-asserted-by":"publisher","first-page":"908","DOI":"10.1038\/s41591-018-0104-9","article-title":"Mechanisms\nof NAFLD development and therapeutic strategies","volume":"24","author":"Friedman","year":"2018","journal-title":"Nat. Med"},{"key":"2026092216092271700_cit34","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1038\/s41575-020-00411-3","article-title":"Role of liver\nsinusoidal endothelial cells in liver diseases","volume":"18","author":"Gracia-Sancho","year":"2021","journal-title":"Nat. Rev. Gastroenterol. Hepatol"},{"issue":"6","key":"2026092216092271700_cit35","doi-asserted-by":"publisher","first-page":"1278","DOI":"10.1016\/j.jhep.2019.02.012","article-title":"Role of liver sinusoidal\nendothelial cells in non-alcoholic\nfatty liver disease","volume":"70","author":"Hammoutene","year":"2019","journal-title":"J. Hepatol"},{"issue":"10","key":"2026092216092271700_cit36","doi-asserted-by":"publisher","first-page":"1130","DOI":"10.1038\/labinvest.2015.95","article-title":"Pivotal role of liver sinusoidal\nendothelial cells in NAFLD\/NASH progression","volume":"95","author":"Miyao","year":"2015","journal-title":"Lab. Invest"},{"issue":"5","key":"2026092216092271700_cit37","doi-asserted-by":"publisher","first-page":"1801809","DOI":"10.1002\/advs.201801809","article-title":"Synergistic\nMicroRNA Therapy in Liver Fibrotic Rat Using MRI-Visible Nanocarrier\nTargeting Hepatic Stellate Cells","volume":"6","author":"Wu","year":"2019","journal-title":"Adv. Sci"},{"issue":"4","key":"2026092216092271700_cit38","doi-asserted-by":"publisher","first-page":"912","DOI":"10.1002\/hep.32181","article-title":"BMS-986263 in patients\nwith advanced hepatic fibrosis:\n36-week results from a randomized, placebo-controlled phase 2 trial","volume":"75","author":"Lawitz","year":"2022","journal-title":"Hepatology"},{"issue":"8","key":"2026092216092271700_cit39","doi-asserted-by":"publisher","first-page":"715","DOI":"10.1080\/1061186X.2017.1322598","article-title":"Specific hepatic stellate cell-penetrating peptide\ntargeted delivery of a KLA peptide reduces collagen accumulation by\ninducing apoptosis","volume":"25","author":"Guo","year":"2017","journal-title":"J. Drug Target"},{"issue":"2","key":"2026092216092271700_cit40","doi-asserted-by":"publisher","first-page":"797","DOI":"10.1124\/jpet.105.100347","article-title":"Enhanced hepatic uptake and bioactivity\nof type alpha1(I) collagen gene promoter-specific triplex-forming\noligonucleotides after conjugation with cholesterol","volume":"317","author":"Cheng","year":"2006","journal-title":"J. Pharmacol. Exp. Ther"},{"issue":"8","key":"2026092216092271700_cit41","doi-asserted-by":"publisher","first-page":"1354","DOI":"10.1111\/j.1476-5381.2009.00261.x","article-title":"Curcumin suppresses\nexpression of low-density lipoprotein (LDL) receptor,\nleading to the inhibition of LDL-induced activation of hepatic stellate\ncells","volume":"157","author":"Kang","year":"2009","journal-title":"Br. J. Pharmacol"},{"issue":"12","key":"2026092216092271700_cit42","doi-asserted-by":"publisher","first-page":"20739","DOI":"10.1021\/acsnano.2c07796","article-title":"Reactive Oxygen Species-Responsive\nPolypeptide Drug\nDelivery System Targeted Activated Hepatic Stellate Cells to Ameliorate\nLiver Fibrosis","volume":"16","author":"Hao","year":"2022","journal-title":"ACS Nano"},{"issue":"6","key":"2026092216092271700_cit43","doi-asserted-by":"publisher","first-page":"4704","DOI":"10.1021\/acsnano.3c06107","article-title":"Antioxidative\nHyaluronic Acid\u2013Bilirubin Nanomedicine Targeting Activated\nHepatic Stellate Cells for Anti-Hepatic-Fibrosis Therapy","volume":"18","author":"Shinn","year":"2024","journal-title":"ACS Nano"},{"issue":"9","key":"2026092216092271700_cit44","doi-asserted-by":"publisher","first-page":"3146","DOI":"10.1021\/acs.molpharmaceut.5b00012","article-title":"Immunoliposomes for\nTargeted Delivery\nof an Antifibrotic Drug","volume":"12","author":"Schuster","year":"2015","journal-title":"Mol. 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