Статья

Supramolecular artificial Nano-AUTACs enable tumor-specific metabolism protein degradation for synergistic immunotherapy

Yazhen WangNational Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu 610064, P. R. ChinaLianyi YangNational Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu 610064, P. R. ChinaC. YanKey Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, West China School of Pharmacy, Sichuan University, Chengdu 610041, P. R. ChinaYufan DuKey Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, West China School of Pharmacy, Sichuan University, Chengdu 610041, P. R. ChinaTinghua LiNational Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu 610064, P. R. ChinaWenqing YangKey Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, West China School of Pharmacy, Sichuan University, Chengdu 610041, P. R. ChinaLei LeiNational Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu 610064, P. R. ChinaBin HeNational Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu 610064, P. R. ChinaHuile GaoKey Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, West China School of Pharmacy, Sichuan University, Chengdu 610041, P. R. ChinaNicholas A. PeppasDepartment of Biomedical Engineering, The University of Texas at Austin, Austin, TX 78712, USAJun CaoNational Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu 610064, P. R. China

2024en

ABI

Аннотация

Autophagy-targeting chimera (AUTAC) has emerged as a powerful modality that can selectively degrade tumor-related pathogenic proteins, but its low bioavailability and nonspecific distribution significantly restrict their therapeutic efficacy. Inspired by the guanine structure of AUTAC molecules, we here report supramolecular artificial Nano-AUTACs (GM NPs) engineered by AUTAC molecule GN [an indoleamine 2,3-dioxygenase (IDO) degrader] and nucleoside analog methotrexate (MTX) through supramolecular interactions for tumor-specific protein degradation. Their nanostructures allow for precise localization and delivery into cancer cells, where the intracellular acidic environment can disrupt the supramolecular interactions to release MTX for eradicating tumor cells, modulating tumor-associated macrophages, activating dendritic cells, and inducing autophagy. Specifically, the induced autophagy facilitates the released GN for degrading immunosuppressive IDO to further enhance effector T cell activity and inhibit tumor growth and metastasis. This study offers a unique strategy for building a nanoplatform to advance the field of AUTAC in tumor immunotherapy.

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Идентификаторы

DOI: 10.1126/sciadv.adn8079

Цитирования и источники

Цитирований: 2Использованных источников: 0

Показатели — AkademScholar