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.
Liu et al. (Wed,) studied this question.