GSH-Responsive Nanoparticles Enhance Hepatocellular Carcinoma Immunotherapy Through Synergistic Effects of Cuproptosis and PI3K Inhibitor Combination.

Cuproptosis, an emerging form of programmed cell death, is capable of inducing mitochondrial dysfunction. Moreover, the PI3K-AKT-mTOR signaling pathway contributes to tumor cell progression by reprogramming mitochondrial morphology and function. In this study, we have designed copper complex nanoparticles (NPCu) and PI3K-AKT-mTOR inhibitor Alpelisib nanoparticles (NPALP) that enhance the efficacy of cuproptosis-based therapies. NPCu triggers mitochondrial dysfunction and promotes the aggregation of lipoylated dihydrolipoamide S-acetyltransferase (DLAT), while NPALP inhibits the PI3K-AKT-mTOR signaling pathway to induce apoptosis. The combination of these two nanoparticles (NPCu+NPALP) effectively activates the antitumor responses in the tumor microenvironment (TME). When combined with an anti-programmed cell death protein 1 antibody (α-PD-1), NPCu+NPALP significantly inhibits tumor progression and activates antitumor immunity, offering a promising strategy for liver cancer treatment.