期刊
ADVANCED SCIENCE
卷 8, 期 13, 页码 -出版社
WILEY
DOI: 10.1002/advs.202100292
关键词
cancer immunotherapy; cascade amplified; CRISPR; Cas9; nano‐ matryoshka; programmable unlocking
资金
- National Natural Science Foundation of China [81771967, 81822025]
- 1.3.5 Project for Disciplines of Excellence, West China Hospital, Sichuan University
The PUN system targets PD-L1 and PTPN2 for permanent, complete and highly responsive immunotherapy. By releasing CRISPR/Cas9 to efficiently disrupt PD-L1 and PTPN2 in tumor cells, it enhances adaptive immune responses.
Immune checkpoint blockade (ICB) is an attractive option in cancer therapy, but its efficacy is still less than expected due to the transient and incomplete blocking and the low responsiveness. Herein, an unprecedented programmable unlocking nano-matryoshka-CRISPR system (PUN) targeting programmed cell death ligand 1 (PD-L1) and protein tyrosine phosphatase N2 (PTPN2) is fabricated for permanent and complete and highly responsive immunotherapy. While PUN is inert at normal physiological conditions, enzyme-abundant tumor microenvironment and preternatural intracellular oxidative stress sequentially trigger programmable unlocking of PUN to realize a nano-matryoshka-like release of CRISPR/Cas9. The successful nucleus localization of CRISPR/Cas9 ensures the highly efficient disruption of PD-L1 and PTPN2 to unleash cascade amplified adaptive immune response via revoking the immune checkpoint effect. PD-L1 downregulation in tumor cells not only disrupts PD-1/PD-L1 interaction to attenuate the immunosurveillance evasion but also spurs potent immune T cell responses to enhance adaptive immunity. Synchronously, inhibition of JAK/STAT pathway is relieved by deleting PTPN2, which promotes tumor susceptibility to CD8(+) T cells depending on IFN-gamma, thus further amplifying adaptive immune responses. Combining these advances together, PUN exhibits optimal antitumor efficiency and long-term immune memory with negligible toxicity, which provides a promising alternative to current ICB therapy.
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