Highly efficient and tumor-selective nanoparticles for dual-targeted immunogene therapy against cancer

Kuan Wei Huang, Fu Fei Hsu, Jiantai Timothy Qiu, Guann Jen Chern, Yi An Lee, Chih Chun Chang, Yu Ting Huang, Yun Chieh Sung, Cheng Chin Chiang, Rui Lin Huang, Chu Chi Lin, Trinh Kieu Dinh, Hsi Chien Huang, Yu Chuan Shih, Donia Alson, Chun Yen Lin, Yung Chang Lin, Po Chiao Chang, Shu Yi Lin, Yunching Chen

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5 Citations (Scopus)

Abstract

While immunotherapy holds great promise for combating cancer, the limited efficacy due to an immunosuppressive tumor microenvironment and systemic toxicity hinder the broader application of cancer immunotherapy. Here, we report a combinatorial immunotherapy approach that uses a highly efficient and tumor-selective gene carrier to improve anticancer efficacy and circumvent the systemic toxicity. In this study, we engineered tumor-targeted lipid-dendrimer-calcium-phosphate (TT-LDCP) nanoparticles (NPs) with thymine-functionalized dendrimers that exhibit not only enhanced gene delivery capacity but also immune adjuvant properties by activating the stimulator of interferon genes (STING)–cGAS pathway. TT-LDCP NPs delivered siRNA against immune checkpoint ligand PD-L1 and immunostimulatory IL-2–encoding plasmid DNA to hepatocellular carcinoma (HCC), increased tumoral infiltration and activation of CD8+ T cells, augmented the efficacy of cancer vaccine immunotherapy, and suppressed HCC progression. Our work presents nanotechnology-enabled dual delivery of siRNA and plasmid DNA that selectively targets and reprograms the immunosuppressive tumor microenvironment to improve cancer immunotherapy.

Original languageEnglish
Article numbereaax5032
Pages (from-to)eaax5032
JournalScience advances
Volume6
Issue number3
DOIs
Publication statusPublished - Jan 15 2020
Externally publishedYes

ASJC Scopus subject areas

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    Huang, K. W., Hsu, F. F., Qiu, J. T., Chern, G. J., Lee, Y. A., Chang, C. C., Huang, Y. T., Sung, Y. C., Chiang, C. C., Huang, R. L., Lin, C. C., Dinh, T. K., Huang, H. C., Shih, Y. C., Alson, D., Lin, C. Y., Lin, Y. C., Chang, P. C., Lin, S. Y., & Chen, Y. (2020). Highly efficient and tumor-selective nanoparticles for dual-targeted immunogene therapy against cancer. Science advances, 6(3), eaax5032. [eaax5032]. https://doi.org/10.1126/sciadv.aax5032