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한국과학기술연구원 (KIST)

Adv. Mater., Jun 19 2024, | https://doi.org/10.1002/adma.202405475 Light-Triggered PROTAC Nanoassemblies for Photodynamic IDO Proteolysis in Cancer Immunotherapy

Jiwoong Choi ¹, Byeongmin Park ¹, Jung Yeon Park ², Dongwon Shin ^1,2, Sangmin Lee ³, Hong Yeol Yoon ¹, Kwangmeyung Kim ⁴, Sun Hwa Kim ^1,2, Yongju Kim ^2,5, Yoosoo Yang ^1,6, Man Kyu Shim ¹

¹Medicinal Materials Research Center, Biomedical Research Division, Korea Institute of Science and Technology (KIST), Seoul, 02792, Republic of Korea.

²KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, 02841, Republic of Korea.

³College of Pharmacy, Graduate School of Pharmaceutical Sciences, Kyung Hee University, Seoul, 02453, Republic of Korea.

⁴College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, 03760, Republic of Korea.

⁵Chemical and Biological Integrative Research Center, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea.

⁶Division of Bio-Medical Science and Technology, KIST School, Korea University of Science and Technology, Seoul, 02792, Republic of Korea.

J. C and B. P contributed equally to this work.

CORRESPONDING AUTHORS: Yongju Kim, Yoosoo Yang, Man Kyu Shim

Abstract

While proteolysis-targeting chimeras (PROTACs) hold great potential for persistently reprogramming the immunosuppressive tumor microenvironment (ITM) via targeted protein degradation, precisely activating them in tumor tissues and preventing uncontrolled proteolysis at off-target sites remain challenging. Herein, we report a light-triggered PROTAC nanoassembly (LPN) for photodynamic indoleamine 2,3-dioxygenase (IDO) proteolysis. The LPN is derived from the self-assembly of prodrug conjugates, which comprise a PROTAC, cathepsin B-specific cleavable peptide linker and photosensitizer, without any additional carrier materials. In colon tumor models, intravenously injected LPNs initially silence the activity of PROTACs and accumulate significantly in targeted tumor tissues due to an enhanced permeability and retention (EPR) effect. Subsequently, the cancer biomarker cathepsin B begins to trigger the release of active PROTACs from the LPNs through enzymatic cleavage of the linkers. Upon light irradiation, tumor cells undergo immunogenic cell death (ICD) induced by photodynamic therapy (PDT) to promote the activation of effector T cells, while the continuous IDO degradation of PROTAC simultaneously blocks tryptophan metabolite-regulated regulatory T cell-mediated immunosuppression. Such LPN-mediated combinatorial photodynamic IDO proteolysis effectively inhibits tumor growth, metastasis and recurrence. Collectively, this study presents a promising nanomedicine, designed to synergize PROTACs with other immunotherapeutic modalities, for more effective and safer cancer immunotherapy. This article is protected by copyright. All rights reserved.

논문정보

형식Research article
게재일2024년 06월 (BRIC 등록일 2024-06-21)
연구진국내 연구진
분야 바이오·의료융합 > 바이오센싱 및 나노바이오물질

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