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Dysregulation of the gut microbiota\u2010bile acid axis plays a pivotal role in MASLD pathogenesis; however, developing targeted therapies that address this complex interplay remains challenging. Here, we present a safe oral delivery system (QW) comprising in situ self\u2010assembled nanofibrous porous microspheres derived from whey protein and quaternized chitosan, which integrates physical adsorption with bio\u2010regulatory functions. In a murine MASLD model, oral QW administration reduced serum ALT (258.6 to 50.3 U\/L) and AST (204.4 to 86.7 U\/L) levels, and decreased hepatic triglyceride (0.54 to 0.18 mmol\/g) and cholesterol (0.12 to 0.05 mmol\/g) content. The NAS score decreased significantly, accompanied by marked histopathological improvements. Multi\u2010omics analysis revealed that QW reshaped gut microbial composition, doubled the relative abundance of Bacteroidetes, modulated bile acid metabolism, and preserved intestinal barrier integrity through reactivation of the hepatic FXR\u2010SHP signaling pathway. This biocompatible, multi\u2010functional oral system offers a promising therapeutic strategy for MASLD and advances the paradigm of gut\u2010liver axis\u2010based interventions for metabolic liver diseases.<\/jats:p>","DOI":"10.1002\/adma.74066","type":"journal-article","created":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T10:22:57Z","timestamp":1784802177000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Biocompatible Quaternized Chitosan\u2010Whey Protein Nanofibrous Porous Microspheres for Multi\u2010Functional Synergistic Regulation of the Gut\u2010Liver Axis in the Treatment of Metabolic Dysfunction\u2010Associated Steatotic Liver Disease"],"prefix":"10.1002","volume":"38","author":[{"given":"Xiao","family":"Cui","sequence":"first","affiliation":[{"name":"Zhongnan Hospital of Wuhan University Institute of Hepatobiliary Diseases of Wuhan University Transplant Center of Wuhan University National Quality Control Center for Donated Organ Procurement Hubei Key Laboratory of Medical Technology on Transplantation Hubei Provincial Clinical Research Center for Natural Polymer Biological Liver Hubei Engineering Center of Natural Polymer\u2010based Medical Materials  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yihui","family":"Huang","sequence":"additional","affiliation":[{"name":"Zhongnan Hospital of Wuhan University Institute of Hepatobiliary Diseases of Wuhan University Transplant Center of Wuhan University National Quality Control Center for Donated Organ Procurement Hubei Key Laboratory of Medical Technology on Transplantation Hubei Provincial Clinical Research Center for Natural Polymer Biological Liver Hubei Engineering Center of Natural Polymer\u2010based Medical Materials  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4634-061X","authenticated-orcid":false,"given":"Zhongshan","family":"Lu","sequence":"additional","affiliation":[{"name":"Zhongnan Hospital of Wuhan University Institute of Hepatobiliary Diseases of Wuhan University Transplant Center of Wuhan University National Quality Control Center for Donated Organ Procurement Hubei Key Laboratory of Medical Technology on Transplantation Hubei Provincial Clinical Research Center for Natural Polymer Biological Liver Hubei Engineering Center of Natural Polymer\u2010based Medical Materials  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Luo","sequence":"additional","affiliation":[{"name":"Zhongnan Hospital of Wuhan University Institute of Hepatobiliary Diseases of Wuhan University Transplant Center of Wuhan University National Quality Control Center for Donated Organ Procurement Hubei Key Laboratory of Medical Technology on Transplantation Hubei Provincial Clinical Research Center for Natural Polymer Biological Liver Hubei Engineering Center of Natural Polymer\u2010based Medical Materials  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-2223-6822","authenticated-orcid":false,"given":"Jian","family":"You","sequence":"additional","affiliation":[{"name":"Zhongnan Hospital of Wuhan University Institute of Hepatobiliary Diseases of Wuhan University Transplant Center of Wuhan University National Quality Control Center for Donated Organ Procurement Hubei Key Laboratory of Medical Technology on Transplantation Hubei Provincial Clinical Research Center for Natural Polymer Biological Liver Hubei Engineering Center of Natural Polymer\u2010based Medical Materials  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3904-6797","authenticated-orcid":false,"given":"Yongsheng","family":"Ma","sequence":"additional","affiliation":[{"name":"Zhongnan Hospital of Wuhan University Institute of Hepatobiliary Diseases of Wuhan University Transplant Center of Wuhan University National Quality Control Center for Donated Organ Procurement Hubei Key Laboratory of Medical Technology on Transplantation Hubei Provincial Clinical Research Center for Natural Polymer Biological Liver Hubei Engineering Center of Natural Polymer\u2010based Medical Materials  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0660-4740","authenticated-orcid":false,"given":"Jie","family":"Cai","sequence":"additional","affiliation":[{"name":"Zhongnan Hospital of Wuhan University Institute of Hepatobiliary Diseases of Wuhan University Transplant Center of Wuhan University National Quality Control Center for Donated Organ Procurement Hubei Key Laboratory of Medical Technology on Transplantation Hubei Provincial Clinical Research Center for Natural Polymer Biological Liver Hubei Engineering Center of Natural Polymer\u2010based Medical Materials  Wuhan China"},{"name":"College of Chemistry &amp; 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