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A multitargeted extracorporeal blood purification combining endotoxin adsorption with histone neutralization may represent a critical therapeutic approach to improve the clinical outcomes of septic patients. However, existing hemoperfusion adsorbents are often heparin-dependent and single-target and exhibit limited hemocompatibility. Herein, we developed self-anticoagulant heparin-grafted chitosan\/cellulose composite microspheres (CSCEHEP) for the simultaneous adsorption of endotoxin and circulating histones. The obtained CSCEHEP microspheres significantly prolonged plasma coagulation time while maintaining excellent hemocompatibility, owing to the heparin coating. In vitro, CSCEHEP microspheres exhibited adsorption capacities of 251.0 EU\/g (81.8% clearance) for endotoxin and 288.6 \u03bcg\/g (62.8% clearance) for histones, respectively. Meanwhile, CSCEHEP microspheres effectively adsorbed histones in whole blood and counteracted histone-induced endothelial and kidney epithelial cytotoxicity, erythrocyte fragility, and thrombocytopenia. In conclusion, CSCEHEP microspheres are promising adsorbents for hemoperfusion to simultaneously remove endotoxins and circulating histones in septic blood.<\/jats:p>","DOI":"10.1021\/acs.biomac.5c01085","type":"journal-article","created":{"date-parts":[[2025,9,25]],"date-time":"2025-09-25T22:40:23Z","timestamp":1758840023000},"page":"6787-6801","source":"Crossref","is-referenced-by-count":10,"title":["Simultaneous Removal of Endotoxin and Circulating\nHistones by Heparin-Grafted Chitosan-Cellulose Composite Microspheres\nfor Multitargeted Hemoperfusion in Septic Blood"],"prefix":"10.1021","volume":"26","author":[{"given":"Yu","family":"Cheng","sequence":"first","affiliation":[{"name":"West China Hospital of Sichuan University , , ,","place":["Chengdu, China, 610041"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Chen","sequence":"additional","affiliation":[{"name":"Sichuan University , , ,","place":["Chengdu, China, 610065"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Song","sequence":"additional","affiliation":[{"name":"University of Science and Technology of China , , ,","place":["Hefei, China, 230026"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luojia","family":"Jiang","sequence":"additional","affiliation":[{"name":"Jiujiang No. 1 People\u2019s Hospital , , ,","place":["Jiujiang, China, 332000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhan","family":"He","sequence":"additional","affiliation":[{"name":"West China Hospital of Sichuan University , , ,","place":["Chengdu, China, 610041"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7364-3731","authenticated-orcid":true,"given":"Yupei","family":"Li","sequence":"additional","affiliation":[{"name":"West China Hospital of Sichuan University , , ,","place":["Chengdu, China, 610041"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2689-0251","authenticated-orcid":true,"given":"Weifeng","family":"Zhao","sequence":"additional","affiliation":[{"name":"Sichuan University , , ,","place":["Chengdu, China, 610065"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baihai","family":"Su","sequence":"additional","affiliation":[{"name":"West China Hospital of Sichuan University , , ,","place":["Chengdu, China, 610041"]},{"name":"West China Hospital of Sichuan University , , ,","place":["Chengdu, China, 610041"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2025,9,25]]},"reference":[{"issue":"8","key":"2026081812191986900_cit1","doi-asserted-by":"publisher","first-page":"801","DOI":"10.1001\/jama.2016.0287","article-title":"The Third\nInternational Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)","volume":"315","author":"Singer","year":"2016","journal-title":"JAMA"},{"issue":"3","key":"2026081812191986900_cit2","doi-asserted-by":"publisher","first-page":"e209","DOI":"10.1097\/CCM.0000000000004155","article-title":"The Epidemiology of Sepsis in Chinese ICUs: A National Cross-Sectional\nSurvey","volume":"48","author":"Xie","year":"2020","journal-title":"Crit. Care Med."},{"issue":"1","key":"2026081812191986900_cit3","doi-asserted-by":"publisher","DOI":"10.3390\/diagnostics13010079","article-title":"Endotoxin\nin Sepsis: Methods for LPS Detection and\nthe Use of Omics Techniques","volume":"13","author":"Virzi\u0300","year":"2023","journal-title":"Diagnostics"},{"issue":"1","key":"2026081812191986900_cit4","doi-asserted-by":"publisher","first-page":"400","DOI":"10.1186\/s13054-023-04690-5","article-title":"The Role of Endotoxin in Septic Shock","volume":"27","author":"Kellum","year":"2023","journal-title":"Crit.\nCare"},{"issue":"10","key":"2026081812191986900_cit5","doi-asserted-by":"publisher","first-page":"2094","DOI":"10.1097\/CCM.0000000000001162","article-title":"Circulating\nHistones Are Major Mediators of Cardiac Injury in Patients With Sepsis*","volume":"43","author":"Alhamdi","year":"2015","journal-title":"Crit. Care Med."},{"key":"2026081812191986900_cit6","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.650184","article-title":"Circulating Histones\nin Sepsis: Potential Outcome Predictors\nand Therapeutic Targets","volume":"12","author":"Li","year":"2021","journal-title":"Front. Immunol."},{"issue":"2","key":"2026081812191986900_cit7","doi-asserted-by":"publisher","first-page":"176","DOI":"10.1164\/rccm.202207-1253OC","article-title":"Clusterin Neutralizes the Inflammatory and Cytotoxic\nProperties of Extracellular Histones in Sepsis","volume":"208","author":"Augusto","year":"2023","journal-title":"Am. J. Respir. Crit. Care Med."},{"issue":"4","key":"2026081812191986900_cit8","doi-asserted-by":"publisher","first-page":"829","DOI":"10.1016\/j.ajpath.2015.11.025","article-title":"Circulating\nExtracellular Histones\nAre Clinically Relevant Mediators of Multiple Organ Injury","volume":"186","author":"Kawai","year":"2016","journal-title":"Am. J. Pathol."},{"issue":"5","key":"2026081812191986900_cit9","doi-asserted-by":"publisher","first-page":"524","DOI":"10.1097\/shk.0b013e31805363c6","article-title":"Daily Variation In Endotoxin Levels\nIs Associated With Increased Organ Failure In Critically Ill Patients","volume":"28","author":"Klein","year":"2007","journal-title":"Shock"},{"issue":"3","key":"2026081812191986900_cit10","doi-asserted-by":"publisher","first-page":"1084","DOI":"10.21037\/apm-20-1011","article-title":"Elevated Plasma\nHistone H4 Level\nPredicts Increased Risk of Mortality in Patients with Sepsis","volume":"9","author":"Lu","year":"2020","journal-title":"Ann. Palliat. 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Biokhimiia"},{"issue":"3","key":"2026081812191986900_cit26","doi-asserted-by":"publisher","first-page":"301","DOI":"10.1134\/S0006297913030139","article-title":"Interaction of N-Acylated and N-Alkylated\nChitosans\nIncluded in Liposomes with Lipopolysaccharide of Gram-Negative Bacteria","volume":"78","author":"Naberezhnykh","year":"2013","journal-title":"Biochemistry"},{"issue":"1","key":"2026081812191986900_cit27","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.bpc.2008.03.006","article-title":"Comparative Study of Electrokinetic\nPotentials and Binding Affinity of Lipopolysaccharides\u2013Chitosan\nComplexes","volume":"136","author":"Davydova","year":"2008","journal-title":"Biophys. Chem."},{"key":"2026081812191986900_cit28","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1438984","article-title":"Emerging Therapeutic Strategies Targeting\nExtracellular Histones\nfor Critical and Inflammatory Diseases: An Updated Narrative Review","volume":"15","author":"Yang","year":"2024","journal-title":"Front. Immunol."},{"issue":"5","key":"2026081812191986900_cit29","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0233644","article-title":"Heparin and\nNon-Anticoagulant Heparin Attenuate Histone-Induced Inflammatory Responses\nin Whole Blood","volume":"15","author":"Hogwood","year":"2020","journal-title":"PLoS One"},{"key":"2026081812191986900_cit30","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1016\/j.ejphar.2018.02.043","article-title":"Chondroitin\nSulfate Protects Vascular Endothelial Cells from Toxicities of Extracellular\nHistones","volume":"826","author":"Nagano","year":"2018","journal-title":"Eur. J. Pharmacol."},{"issue":"5","key":"2026081812191986900_cit31","doi-asserted-by":"publisher","first-page":"2495","DOI":"10.4049\/jimmunol.1203181","article-title":"Human CRP Defends\nagainst the Toxicity of Circulating Histones","volume":"191","author":"Abrams","year":"2013","journal-title":"J. Immunol."},{"issue":"1","key":"2026081812191986900_cit32","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1097\/ALN.0000000000000429","article-title":"Extracellular Histones\nPlay an Inflammatory Role in\nAcid Aspiration-Induced Acute Respiratory Distress Syndrome","volume":"122","author":"Zhang","year":"2015","journal-title":"Anesthesiology"},{"issue":"1","key":"2026081812191986900_cit33","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-20231-y","article-title":"Neutralizing the Pathological Effects of Extracellular\nHistones with Small Polyanions","volume":"11","author":"Meara","year":"2020","journal-title":"Nat. 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Polym."},{"key":"2026081812191986900_cit46","doi-asserted-by":"publisher","DOI":"10.1016\/j.memsci.2019.117706","article-title":"Heparinized\nThin-Film Composite Membranes with Sub-Micron\nRidge Structure for Efficient Hemodialysis","volume":"599","author":"Yu","year":"2020","journal-title":"J. Membr. Sci."},{"issue":"8","key":"2026081812191986900_cit47","doi-asserted-by":"publisher","first-page":"2247","DOI":"10.1016\/j.jtha.2024.05.009","article-title":"Fibrinogen Binding to Histones in\nCirculation Protects\nagainst Adverse Cellular and Clinical Outcomes","volume":"22","author":"Toh","year":"2024","journal-title":"J. Thromb. Haemostasis"},{"issue":"1","key":"2026081812191986900_cit48","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1016\/j.thromres.2013.04.018","article-title":"Histone Induced\nPlatelet Aggregation Is Inhibited by\nNormal Albumin","volume":"132","author":"Lam","year":"2013","journal-title":"Thromb. 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