Comparative analysis of metabolome and transcriptomes to explore the inhibited influence of sonodynamic therapy combined with lonidamine on hepatocellular carcinoma

Sonodynamic therapy (SDT) has emerged as a promising approach for treating hepatocellular carcinoma (HCC) by combining sonosensitizers with low-intensity ultrasound. However, SDT alone could not achieve satisfactory results. Here, we developed novel nanobubbles loaded with hematoporphyrin monomethyl ether (HMME@NBs) and evaluated its therapeutic potential in combination with the glycolytic inhibitor lonidamine (LND) against HCC. The HMME@NBs was successfully prepared with particle size of 410.58 ± 20.07 nm and zeta potential at -8.38 ± 1.12mV. The encapsulation efficiency and loading efficiency of HMME was 80.6% and 7.12%, respectively. Both <i>in vitro</i> and <i>in vivo</i> studies demonstrated that while SDT and LND monotherapies inhibited the growth of HepG2 cells and xenograft tumors in nude mice, the combination therapy exhibited the most significant inhibitory effect. Multi-omics analysis of tumor tissues revealed substantial alterations in metabolites and gene expression, with key pathways such as glutathione metabolism implicated in the treatment response. Our findings highlight the enhanced antitumor efficacy of HMME@NBs-mediated SDT combined with LND, supported by mechanistic insights from transcriptomic and metabolomic profiling. This synergistic strategy holds great potential for HCC treatment.