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It occurred in approximately 40% of acute liver failure cases and affected 30%\u201345% of patients with chronic liver failure or decompensated cirrhosis. Hyperammonemia is widely recognized as a central pathogenic factor in the pathogenesis of HE. Rifaximin (RIF), a non\u2010absorbable oral antibiotic, was widely used to manage HE by modulating gut microbiota and reducing ammonia production. However, its clinical efficacy remained suboptimal due to poor aqueous solubility, limited dispersibility, and inadequate gastrointestinal retention. These limitations were further exacerbated in severe cases, owing to restricted oral dosing, recurrence associated with poor adherence, and potential risks of antimicrobial resistance and infection\u2010related adverse events. This study presented a microalgae\u2010nanoparticle hybrid system (SP@RIF) for drug delivery, in which RIF\u2010encapsulated nanoparticles (RIFnano) were electrostatically loaded onto the surface of\n                    <jats:italic>Spirulina platensis<\/jats:italic>\n                    (SP), aiming to improve the oral delivery and therapeutic efficiency in HE treatment. RIFnano exhibited significantly enhanced antibacterial activity compared to free RIF. SP@RIF demonstrated prolonged gastrointestinal retention and sustained drug release profiles. In mouse models of HE, oral administration of SP@RIF markedly reduced systemic ammonia levels and improved behavioral outcomes. Furthermore, SP@RIF enhanced intestinal barrier function, attenuated systemic inflammation and neuroinflammation, ameliorated cognitive impairments, and modulated the gut microbiota. Importantly, these therapeutic benefits were achieved without observable toxicity. These findings highlight SP@RIF as a potential therapeutic strategy for treating HE.\n                  <\/jats:p>","DOI":"10.1002\/advs.76443","type":"journal-article","created":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T12:56:20Z","timestamp":1785502580000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Microalgae Hybrid Biosystem for Enhanced Oral Delivery of Rifaximin in Hepatic Encephalopathy Treatment"],"prefix":"10.1002","volume":"13","author":[{"given":"Kaiyue","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Surgery and International School of Medicine International Institutes of Medicine the Fourth Affiliated Hospital of School of Medicine Zhejiang University  Yiwu China"},{"name":"Department of Radiology Sir Run Run Shaw Hospital Zhejiang University School of Medicine  Hangzhou 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the Fourth Affiliated Hospital of School of Medicine Zhejiang University  Yiwu China"},{"name":"Department of Surgery The Second Affiliated Hospital Zhejiang University School of Medicine  Hangzhou 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