Key Laboratory of Biomedical Polymers of Ministry of Education, Department of Chemistry, Wuhan University, Wuhan, 430072, P. R. China.
School of Life Sciences, Anhui Medical University, Hefei, 230032, P. R. China.
Adv Mater. 2020 Apr;32(17):e2000208. doi: 10.1002/adma.202000208. Epub 2020 Mar 9.
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.
有效逆转肿瘤免疫抑制在癌症治疗中至关重要。构建了一种多功能递药载体，可有效递呈 CRISPR-Cas9 质粒用于β-连环蛋白敲除，从而逆转肿瘤免疫抑制。多功能化递药载体用结合了适体的透明质酸和肽结合的透明质酸进行修饰，将 AS1411 的肿瘤细胞/核靶向功能与 TAT-NLS 的细胞穿透/核转位功能相结合。由于质粒在恶性细胞核中的富集显著增强，基因组编辑系统可诱导有效的β-连环蛋白敲除并抑制 Wnt/β-连环蛋白通路，导致参与肿瘤进展和免疫抑制的蛋白明显下调。编辑后的肿瘤细胞中程序性死亡配体 1（PD-L1）的下调不仅释放了 PD-1/PD-L1 制动器，从而提高了 CD8 T 细胞对癌症的杀伤能力，还增强了免疫细胞的抗肿瘤免疫反应。这为逆转肿瘤免疫抑制以及恢复免疫监视和激活抗肿瘤免疫提供了一种简便的策略。
