Trojan‐Horse Strategy Targeting the Gut‐Liver Axis Modulates Gut Microbiome and Reshapes Microenvironment for Orthotopic Hepatocellular Carcinoma Therapy

Abstract Reversing the hepatic inflammatory and immunosuppressive microenvironment caused by gut microbiota‐derived lipopolysaccharides (LPS), accumulating to the liver through the gut‐liver axis, is crucial for suppressing hepatocellular carcinoma (HCC) and metastasis. However, synergistically manipulating LPS‐induced inflammation and gut microbiota remains a daunting task. Herein, a Trojan‐horse strategy is proposed using an oral dextran‐carbenoxolone (DEX‐CBX) conjugate, which combines prebiotic and glycyrrhetinic acid (GA) homologs, to targeted delivery GA to HCC through the gut‐liver axis for simultaneous modulation of hepatic inflammation and gut microbiota. In the orthotopic HCC model, a 95–45% reduction in the relative abundances of LPS‐associated microbiota is observed, especially Helicobacter , caused by DEX‐CBX treatment over phosphate‐buffered saline (PBS) treatment. Notably, a dramatic increase (37‐fold over PBS) in the abundance of Akkermansia , which is known to strengthen systemic immune response, is detected. Furthermore, DEX‐CBX significantly increased natural killer T cells (5.7‐fold) and CD8 + T cells (3.9‐fold) as well as decreased M2 macrophages (59% reduction) over PBS treatment, resulting in a tumor suppression rate of 85.4%. DEX‐CBX is anticipated to offer a novel strategy to precisely modulate hepatic inflammation and the gut microbiota to address both the symptoms and root causes of LPS‐induced immunosuppression in HCC.