Aptamer/Peptide-Functionalized Genome-Editing System for Effective Immune Restoration through Reversal of PD-L1-Mediated Cancer Immunosuppression.
Xiao-Yan HeXiao-He RenYan PengJian-Ping ZhangShu-Lun AiBo-Ya LiuChang XuSi-Xue ChengPublished in: Advanced materials (Deerfield Beach, Fla.) (2020)
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.
Keyphrases
- crispr cas
- genome editing
- hyaluronic acid
- cancer therapy
- cell proliferation
- single cell
- immune response
- cell therapy
- papillary thyroid
- stem cells
- gold nanoparticles
- epithelial mesenchymal transition
- drug delivery
- escherichia coli
- photodynamic therapy
- signaling pathway
- mesenchymal stem cells
- sensitive detection
- toll like receptor
- molecularly imprinted
- high resolution
- poor prognosis
- dendritic cells
- squamous cell carcinoma
- mass spectrometry
- young adults
- magnetic nanoparticles
- childhood cancer
- wild type