TY - JOUR
T1 - Targeted Degradation of PD-L1 and Activation of the STING Pathway by Carbon-Dot-Based PROTACs for Cancer Immunotherapy
AU - Su, Wen
AU - Tan, Mixiao
AU - Wang, Zhihang
AU - Zhang, Jie
AU - Huang, Wenping
AU - Song, Haohao
AU - Wang, Xinye
AU - Ran, Haitao
AU - Gao, Yanfeng
AU - Nie, Guangjun
AU - Wang, Hai
N1 - Funding Information:
This work was financially supported by the National Key R&D Program of China (2021YFA1201200), the National Natural Science Foundation of China (31971307), and the China Postdoctoral Science Foundation (2021M690803). We thank the Core Facility of Center of Biomedical Analysis, Tsinghua University for assistance with confocal microscopy and flow cytometry analysis.
Publisher Copyright:
© 2023 Wiley-VCH GmbH.
PY - 2023/3/6
Y1 - 2023/3/6
N2 - Proteolysis targeting chimeras (PROTACs) technology is an emerging approach to degrade disease-associated proteins. Here, we report carbon-dot (CD)-based PROTACs (CDTACs) that degrade membrane proteins via the ubiquitin-proteasome system. CDTACs can bind to programmed cell death ligand 1 (PD-L1), recruit cereblon (CRBN) to induce PD-L1 ubiquitination, and degrade them with proteasomes. Fasting-mimicking diet (FMD) is also used to enhance the cellular uptake and proteasome activity. More than 99 % or 90 % of PD-L1 in CT26 or B16-F10 tumor cells can be degraded by CDTACs, respectively. Furthermore, CDTACs can activate the stimulator of interferon genes (STING) pathway to trigger immune responses. Thus, CDTACs with FMD treatment effectively inhibit the growth of CT26 and B16-F10 tumors. Compared with small-molecule-based PROTACs, CDTACs offer several advantages, such as efficient membrane protein degradation, targeted tumor accumulation, immune system activation, and in vivo detection.
AB - Proteolysis targeting chimeras (PROTACs) technology is an emerging approach to degrade disease-associated proteins. Here, we report carbon-dot (CD)-based PROTACs (CDTACs) that degrade membrane proteins via the ubiquitin-proteasome system. CDTACs can bind to programmed cell death ligand 1 (PD-L1), recruit cereblon (CRBN) to induce PD-L1 ubiquitination, and degrade them with proteasomes. Fasting-mimicking diet (FMD) is also used to enhance the cellular uptake and proteasome activity. More than 99 % or 90 % of PD-L1 in CT26 or B16-F10 tumor cells can be degraded by CDTACs, respectively. Furthermore, CDTACs can activate the stimulator of interferon genes (STING) pathway to trigger immune responses. Thus, CDTACs with FMD treatment effectively inhibit the growth of CT26 and B16-F10 tumors. Compared with small-molecule-based PROTACs, CDTACs offer several advantages, such as efficient membrane protein degradation, targeted tumor accumulation, immune system activation, and in vivo detection.
KW - Cancer Therapy
KW - Carbon Dots
KW - Nanomedicine
KW - PROTACs
KW - Proteins/metabolism
KW - Proteasome Endopeptidase Complex/metabolism
KW - Ubiquitin-Protein Ligases/metabolism
KW - B7-H1 Antigen/metabolism
KW - Proteolysis
KW - Humans
KW - Immunotherapy
KW - Neoplasms/drug therapy
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U2 - 10.1002/anie.202218128
DO - 10.1002/anie.202218128
M3 - Article
C2 - 36647763
AN - SCOPUS:85147436383
SN - 1433-7851
VL - 62
SP - e202218128
JO - Angewandte Chemie - International Edition
JF - Angewandte Chemie - International Edition
IS - 11
M1 - e202218128
ER -