Genome editing of PD-L1 mediated by nucleobase-modified polyamidoamine for cancer immunotherapy.

Abstract

Immune checkpoint blockade therapy against programmed death protein-1 and its ligand (PD-1/PD-L1) has been accepted as a promising approach to activate the immune system's anti-tumor response. Although small interfering RNA (siRNA) or antibodies can block the PD-1/PD-L1 pathway, the effect of this blockade is temporary and reversible. Here, we developed a nano-delivery system to achieve permanent disruption of the PD-L1 gene based on Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR-associated nuclease 9 (Cas9) gene editing technology. In this system, the CRISPR/Cas9 plasmid was delivered into melanoma B16F10 cells using a nucleobase-modified polyamidoamine (PAMAM) derivative namely AP-PAMAM, which was constructed through the modification with 2-amino-6-chloropurine. Meanwhile, the carrier could efficiently facilitate the endosomal escape of CRISPR/Cas9 plasmid and thereby inhibit PD-L1 expression in cancer cells. Moreover, the intravenous injection of AP-PAMAM/plasmid nanoparticles could recruit and activate CD8+ T cells at the tumor site, promoting the secretion of cytokines and the killing of tumor cells. Overall, this nano-delivery system for genome editing provided a promising strategy to block the PD-1/PD-L1 pathway and obtain effective tumor immunotherapy.

• Authors: Simeng Wei, Xinxin Shao, Yong Liu, Boyu Xiong, Pengfei Cui, Ziling Liu, Quanshun Li
• Journal: Journal of materials chemistry. B (J Mater Chem B) Vol. 10 Issue 8 Pg. 1291-1300 (02 23 2022) ISSN: 2050-7518 [Electronic] England
• PMID: 35141737 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• B7-H1 Antigen
• Poly(amidoamine)
• Polyamines
• Programmed Cell Death 1 Receptor
• RNA, Small Interfering

Topics

• B7-H1 Antigen (genetics, metabolism)
• CD8-Positive T-Lymphocytes (metabolism)
• Cell Line, Tumor
• Gene Editing
• Immunotherapy
• Neoplasms (genetics, therapy)
• Polyamines
• Programmed Cell Death 1 Receptor
• RNA, Small Interfering (pharmacology)