Anti-tumor immunity and ferroptosis of hepatocellular carcinoma are enhanced by combined therapy of sorafenib and delivering modified GO-based PD-L1 siRNAs
- Biomater Adv. 2022 May:136:212761. doi: 10.1016/j.bioadv.2022.212761.
- 1. National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Science, Hunan Normal University, Changsha 410081, China.
- 2. College of Chemistry, Hunan Normal University, Changsha 410081, China.
- 3. Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, Hunan Normal University, Changsha 410013, China.
- 4. Department of Physics, Department of Materials Science and Engineering, and Department of Biomedical Engineering, City University of Hong Kong, Tat Chee Avenue, Kowloon, Hong Kong, China.
- 5. College of Engineering and Design, Hunan Normal University, Changsha 410081, China. Electronic address: [email protected].
- 6. National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Science, Hunan Normal University, Changsha 410081, China. Electronic address: [email protected].
- 7. National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Science, Hunan Normal University, Changsha 410081, China. Electronic address: [email protected].
Programmed cell death receptor ligand 1 (PD-L1)/PD-1 signaling has been exploited to design inhibitors that deliver promising clinical outcome albeit with limited efficacy. Herein, we prepare graphene oxide (GO)-PEI-PEG with low cytotoxicity and long stability and GO-PEI-PEG delivers PD-L1 siRNAs to hepatocellular carcinoma (HCC) cells by the endocytosis-lysosome pathway. The functional GO-PEI-PEG/PD-L1 siRNAs decrease PD-L1 and PD-1 abundance, increase pro-inflammation cytokine IFN-γ and TNF-α release, and improve the proliferation activity of Jurkat T cells. Since GO-PEI-PEG targets the mouse liver effectively, the intrahepatic tumors in C57BL/6 mice are treated with GO-PEI-PEG/Pd-l1 siRNAs via the tail vein, resulting in shrinkage of the HCC tumors and boosting the anti-tumor efficacy in combination with oral sorafenib. A single treatment improves the total CD3+ and cytotoxic CD8+ T cell infiltration in the HCC tumor tissues and even spleen and upregulates the expression of Perforin, Gzmb, Ifng, Il-1b and Tnfa in the tumors after the combined treatment. Both the single and combined treatments enhance Reactive Oxygen Species (ROS) accumulation, and improved HCC Ferroptosis. The results suggest that GO-PEI-PEG delivered PD-L1 siRNAs combined with oral sorafenib can activate the adaptive immunity and tumor Ferroptosis and reveal an effective therapy to treat advanced HCC patients.