Pt-TiO2 mesoporous nanosystem co-delivering phlorezin enables synergistic sonodynamic-chemoimmunotherapy for hepatocellular carcinoma via directly targeting DDX5 and metabolic reprogramming modulation

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.