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 identified 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 efficient 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 methods, multimodal imaging corroborates a marked enhancement in local drug retention and tumor suppression. Importantly, the incorporation of Rhein-mediated synergistic 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 presentation to CD8+ T cells for tumor killing. Together, these findings reveal a novel strategy for the application of self-assembled Rhein nanofiber-stabilized lipiodol emulsion to control metabolic signaling and immunoactivation in TACE.