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Programmable Unlocking Nano‐Matryoshka‐CRISPR Precisely Reverses Immunosuppression to Unleash Cascade Amplified Adaptive Immune Response

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 c...

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Autores principales: Yang, Jin, Li, Zhike, Shen, Meiling, Wang, Yan, Wang, Li, Li, Jiamiao, Yang, Wen, Li, Jie, Li, Haijun, Wang, Xinxin, Wu, Qinjie, Gong, Changyang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8261501/
https://www.ncbi.nlm.nih.gov/pubmed/34258164
http://dx.doi.org/10.1002/advs.202100292
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author Yang, Jin
Li, Zhike
Shen, Meiling
Wang, Yan
Wang, Li
Li, Jiamiao
Yang, Wen
Li, Jie
Li, Haijun
Wang, Xinxin
Wu, Qinjie
Gong, Changyang
author_facet Yang, Jin
Li, Zhike
Shen, Meiling
Wang, Yan
Wang, Li
Li, Jiamiao
Yang, Wen
Li, Jie
Li, Haijun
Wang, Xinxin
Wu, Qinjie
Gong, Changyang
author_sort Yang, Jin
collection PubMed
description 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‐γ, 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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spelling pubmed-82615012021-07-12 Programmable Unlocking Nano‐Matryoshka‐CRISPR Precisely Reverses Immunosuppression to Unleash Cascade Amplified Adaptive Immune Response Yang, Jin Li, Zhike Shen, Meiling Wang, Yan Wang, Li Li, Jiamiao Yang, Wen Li, Jie Li, Haijun Wang, Xinxin Wu, Qinjie Gong, Changyang Adv Sci (Weinh) Research Articles 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‐γ, 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. John Wiley and Sons Inc. 2021-05-14 /pmc/articles/PMC8261501/ /pubmed/34258164 http://dx.doi.org/10.1002/advs.202100292 Text en © 2021 The Authors. Advanced Science published by Wiley‐VCH GmbH https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Yang, Jin
Li, Zhike
Shen, Meiling
Wang, Yan
Wang, Li
Li, Jiamiao
Yang, Wen
Li, Jie
Li, Haijun
Wang, Xinxin
Wu, Qinjie
Gong, Changyang
Programmable Unlocking Nano‐Matryoshka‐CRISPR Precisely Reverses Immunosuppression to Unleash Cascade Amplified Adaptive Immune Response
title Programmable Unlocking Nano‐Matryoshka‐CRISPR Precisely Reverses Immunosuppression to Unleash Cascade Amplified Adaptive Immune Response
title_full Programmable Unlocking Nano‐Matryoshka‐CRISPR Precisely Reverses Immunosuppression to Unleash Cascade Amplified Adaptive Immune Response
title_fullStr Programmable Unlocking Nano‐Matryoshka‐CRISPR Precisely Reverses Immunosuppression to Unleash Cascade Amplified Adaptive Immune Response
title_full_unstemmed Programmable Unlocking Nano‐Matryoshka‐CRISPR Precisely Reverses Immunosuppression to Unleash Cascade Amplified Adaptive Immune Response
title_short Programmable Unlocking Nano‐Matryoshka‐CRISPR Precisely Reverses Immunosuppression to Unleash Cascade Amplified Adaptive Immune Response
title_sort programmable unlocking nano‐matryoshka‐crispr precisely reverses immunosuppression to unleash cascade amplified adaptive immune response
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8261501/
https://www.ncbi.nlm.nih.gov/pubmed/34258164
http://dx.doi.org/10.1002/advs.202100292
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