Aptamer/Peptide-Functionalized Genome-Editing System for Effective Immune Restoration through Reversal of PD-L1-Mediated Cancer Immunosuppression

Advanced Materials
Xiao-Yan HeSi-Xue Cheng

Abstract

Effective reversal of tumor immunosuppression is of critical importance in cancer therapy. A multifunctional delivery vector that can effectively deliver CRISPR-Cas9 plasmid for β-catenin knockout to reverse tumor immunosuppression is constructed. The multi-functionalized delivery vector is decorated with aptamer-conjugated hyaluronic acid and peptide-conjugated hyaluronic acid to combine the tumor cell/nuclear targeting function of AS1411 with the cell penetrating/nuclear translocation function of TAT-NLS. Due to the significantly enhanced plasmid enrichment in malignant cell nuclei, the genome editing system can induce effective β-catenin knockout and suppress Wnt/β-catenin pathway, resulting in notably downregulated proteins involved in tumor progression and immunosuppression. Programmed death-ligand 1 (PD-L1) downregulation in edited tumor cells not only releases the PD-1/PD-L1 brake to improve the cancer killing capability of CD8+ T cells, but also enhances antitumor immune responses of immune cells. This provides a facile strategy to reverse tumor immunosuppression and to restore immunosurveillance and activate anti-tumor immunity.

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Citations

Oct 9, 2020·International Journal of Molecular Sciences·Karim ShalabyOmar El-Agnaf
Dec 4, 2020·International Journal of Molecular Sciences·Zhaoying Fu, Jim Xiang
Jan 28, 2021·Journal of Controlled Release : Official Journal of the Controlled Release Society·Can LeiTao Zou
Jan 6, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Lingyun LiWeizhi Wang
Nov 22, 2020·Journal of Materials Chemistry. B, Materials for Biology and Medicine·Yu TaoMingqiang Li
Oct 21, 2020·Advanced Drug Delivery Reviews·Ke LiXian-Zheng Zhang
Mar 26, 2021·Molecular Cancer·Tina BriolayNicolas Boisgerault
Jun 12, 2021·Biomaterials Science·Jingyue YanYizhou Dong
Jul 30, 2021·Advanced Drug Delivery Reviews·Xiaoyu XuHongbo Zhang

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