Microalgae Hybrid Biosystem for Enhanced Oral Delivery of Rifaximin in Hepatic Encephalopathy Treatment

ABSTRACT

Hepatic encephalopathy (HE) is a serious neuropsychiatric complication of acute or chronic liver failure. It occurred in approximately 40% of acute liver failure cases and affected 30%–45% 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‐absorbable 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‐related adverse events. This study presented a microalgae‐nanoparticle hybrid system (SP@RIF) for drug delivery, in which RIF‐encapsulated nanoparticles (RIFnano) were electrostatically loaded onto the surface of Spirulina platensis (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.