Pt‐TiO ₂ mesoporous nanosystem co‐delivering phlorezin enables synergistic sonodynamic‐chemoimmunotherapy for hepatocellular carcinoma via directly targeting DDX5 and metabolic reprogramming modulation

Abstract Hepatocellular carcinoma (HCC), ranking as the third leading cause of cancer‐related mortality globally, continues to pose significant therapeutic challenges. Here, we developed an innovative nanosystem, Phl@PT, based on Pt‐TiO 2 nanoparticles for the co‐delivery of Phlorezin, presenting a novel approach for HCC treatment through sonodynamic therapy (SDT). Phl@PT demonstrated remarkable efficacy in inducing mitochondrial membrane potential collapse and cristae damage in vitro. Transcriptomic sequencing analysis revealed that Phl@PT treatment led to the downregulation of key genes: CLDN6 , involved in the cell adhesion molecules pathway, and BCKDHB and SUCLG2 , associated with propanoate metabolism. Through a comprehensive target fishing strategy combined with Bio‐Layer Interferometry analysis, we identified DDX5, a DEAD‐box RNA helicase, as a novel target protein of Phlorezin, which plays a crucial role in tumor progression and prognosis. In vivo studies demonstrated that US‐activated Phl@PT not only effectively inhibited HCC growth in murine models but also activated CD8 + /CD4 + T cells, promoted dendritic cell maturation, and enhanced the expression of key immune cytokines including TNF‐α, IL‐12, and IFN‐γ, thereby establishing a robust immunotherapeutic response. Collectively, our findings demonstrate that the Pt‐TiO 2 mesoporous nanoagent co‐delivering phlorezin represents a promising therapeutic platform for HCC treatment through synergistic sonodynamic‐chemo‐immunotherapy.