Marine-derived oral nanovesicles from Sargassum fusiforme ameliorate steatohepatitis by activating the HO-1 pathway to inhibit NF-κB signaling and restore small intestinal homeostasis

BACKGROUND: Marine algae, notably the edible brown seaweed Sargassum fusiforme (Hijiki), harbor a vast repertoire of bioactive molecules with potent anti-inflammatory and metabolic regulatory properties. However, their clinical translation is severely hampered by poor systemic bioavailability and susceptibility to gastrointestinal degradation. To circumvent these bottlenecks, we engineered Sargassum fusiforme-derived nanovesicles (SF-NVs) as a robust, intrinsic oral delivery platform. These nanovesicles effectively encapsulate and protect bioactive cargos, significantly augmenting their stability and therapeutic efficacy within the hostile gut environment. RESULTS: In this study, bioactive nanovesicles were isolated from the edible brown alga Sargassum fusiforme using two complementary methodologies: sucrose gradient ultracentrifugation for high-purity characterization and hollow fiber membrane concentration for scalable, clinically translatable production. The resulting Sargassum fusiforme-derived nanovesicles (SF-NVs) exhibited a spherical morphology (mean diameter:120.8 ± 5.0 nm diameter) and a stable zeta potential (-45.2 ± 1.3 mV). Lipidomic profiling revealed a signature dominated by Hex1Cer (31%), notably distinct from terrestrial plant vesicles by its RNA-free composition. Mechanistically, in vitro assays demonstrated that SF-NVs were internalized by macrophages, where they triggered the upregulation of heme oxygenase-1 (HO-1). This activation served as a critical checkpoint, subsequently blocking the NF-κB signaling cascade by suppressing IKKα/IκBα phosphorylation and p65 nuclear translocation, thereby attenuating pro-inflammatory cytokine production. Elemol was identified as a key bioactive constituent contributing to this anti-inflammatory activity. In HFD-induced MASH models, oral administration of hollow fiber membrane concentrate (HFMC) successfully ameliorated steatosis, liver injury, and systemic inflammation. Crucially, the therapeutic efficacy was driven by the restoration of small intestinal homeostasis; HFMC suppressed HFD-induced chronic intestinal inflammation and enhanced mucosal barrier integrity. By mitigating the inflammatory surge at the enteric level and modulating luminal lipid levels, SF-NVs reprogrammed hepatic lipid metabolism-suppressing lipogenesis while promoting β-oxidation and lipid export. These findings suggest that SF-NVs act through the HO-1-NF-κB axis to rectify gut-liver axis dysregulation, offering a potent marine-derived strategy for MASH treatment. CONCLUSION: This study provides the first evidence that SF-NVs can effectively treat MASH by orchestrating the HO-1-mediated anti-inflammatory response and restoring small intestinal homeostasis. Our findings define a novel paradigm for leveraging marine-derived nanotechnology to address metabolic crises, bridging the gap between sustainable marine resource utilization and next-generation oral therapeutics for inflammatory diseases.