Disturbing mitochondrial functionalities on the utilization of Lenvatinib-conjugated Gallium (III) nanocomposites as therapeutic avenue to potentiate hepatocellular carcinoma inhibition

Lenvatinib, an effective treatment for hepatocellular carcinoma (HCC), faces limitations due to mitochondrial function shift-induced energy metabolism reprogramming. Therefore, interfering with mitochondrial energy metabolism to enhance the curative effect of lenvatinib may represent a promising strategy. In this study, an indocyanine green (ICG)-templated self-assembling nanotherapeutic, lenvatinib-Ga (LGa), containing lenvatinib and gallium (III) ions, was constructed for combination therapy of HCC. LGa significantly enhanced the ability to induce HCC cell death. Subsequent investigations into mitochondrial dysfunction revealed that LGa increased intracellular levels of mitochondrial reactive oxygen species (ROS), leading to the collapse of mitochondrial membrane potential, impairments in adenosine triphosphate (ATP) synthesis and cellular respiration, as well as downregulation of Bcl-2 and activation of cleaved-caspase 3. Additionally, LGa upregulated endoplasmic reticulum (ER) stress-related protein expression (activating transcription factor 4 (ATF4), eukaryotic initiation factor 2 alpha (EIF2α), and C/EBP homologous protein (CHOP)), boosting calcium ion (Ca 2+ ) overload. These effects promoted HCC cell apoptosis and suppressed tumor growth in vivo . Moreover, LGa was further able to induce immunogenic cell death (ICD), promoting dendritic cell (DC) maturation. Simultaneously, LGa promoted the release of mitochondrial DNA (mtDNA), activating the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway and subsequently triggering a DC-mediated immune response. Combined with anti-PD-1 antibody immunotherapy, LGa achieved synergistic anti-tumor effects. Our findings suggest LGa could be a promising therapeutic approach for HCC.