Rhein-based Pickering emulsion for hepatocellular carcinoma:Shaping the metabolic signaling and immunoactivation in transarterial chemoembolization

The efficacy of transarterial chemoembolization(TACE)has been limited by insufficient embolization and a high incidence of tumor recurrence.Herein,we iden-tified that aberrant metabolic reprogramming and immunosuppression contribute to TACE refractoriness and Rhein,as a potential glycolytic metabolism inhibitor and immunoactivation inducer,was optimized to sensitize tumors to TACE therapy.To achieve efficient embolization,we developed an oil-in-water lipiodol embolic emulsion by stabilizing the self-assembled Rhein nanogel.The assembled Rhein exhibited a nanofiber network,and its integration enhanced the mechanical stability and viscoelasticity of the lipiodol embolic agent.With the synergistic advantages of solid and liquid embolic agents,this carrier-free Pickering emulsion exhibits effi-cient embolization and sustained drug release in models of unilateral renal artery embolization,rabbit ear tumor embolization,rabbit orthotopic liver cancer,and rat orthotopic liver cancer.Compared to conventional three-way catheter mixing meth-ods,multimodal imaging corroborates a marked enhancement in local drug retention and tumor suppression.Importantly,the incorporation of Rhein-mediated syner-gistic immunoembolization in this strategy achieved efficient embolization while robustly activating anti-tumor immune responses,including inducing immunogenic cell death,dendritic cell activation,and major histocompatibility complex class I pre-sentation to CD8+T cells for tumor killing.Together,thesefindings reveal a novel strategy for the application of self-assembled Rhein nanofiber-stabilized lipiodol emulsion to control metabolic signaling and immunoactivation in TACE.