A stepwise responsive Au-SS-PEG/Sor/ATPaptamer/LHRH-MPGΔNLS drug delivery vector system for overcoming drug resistance in immunotherapy of hepatocellular carcinoma.

Despite the progress made in novel immunotherapy for hepatocellular carcinoma (HCC), drug resistance remains a challenging problem. In this study, we developed a stepwise nanodrug delivery system, known as Au-SS-PEG/Sor/ATP_aptamer/LHRH-MPG^ΔNLS, to adapt to the high concentrations of glutathione (GSH) and adenine nucleoside triphosphate/adenosines (ATP/ADO) found in cancer cells and the tumor microenvironment (TME). This system utilizes novel Au nanoclusters conjugated with disulfide-linked PEG as vectors to transport sorafenib (Sor) and an ATP-binding nucleic acid aptamer (ATP_apt). It can enter HCC cells through luteinizing hormone-releasing hormone (LHRH)-MPG^ΔNLS (LM). Within the cells, the disulfide bonds of the nanoclusters are cleaved by the high levels of GSH, leading to the release of Sor/ATPapt. This release can be further triggered by ATP/ADO, resulting in a stepwise drug release mechanism. Furthermore, this nanodrug system has exhibited the ability to overcome αPD-1 resistance in HCC tumors. In summary, our novel drug delivery system demonstrates a dramatic anti-HCC effect and holds great potential for treating HCC patients.