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한국과학기술연구원 (KIST)

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Signal Transduct. Target. Ther., 09 July 2026 | https://doi.org/10.1038/s41392-026-02872-5 Switching tumor-derived extracellular vesicles off and on via targeted proteolysis to shift toward immunogenic phenotypes

Yeongji Jang¹, Byeongmin Park^1,2, Jiwoong Choi³, Do Young Jin⁴, Eun Hye Kim⁵, Hochung Jang⁵, Jae-Hyeon Lee⁶, Eunbyeol Ko^1,7,8,9, Dongwon Shin^1,2, Kyungsu Kim¹, Woohyeong Lee¹, Ansoo Lee^1,10, Myung Chul Lee^1,10, In-Cheol Sun¹, Hong Yeol Yoon^1,10, Sangmin Lee^7,8,9, Sun Hwa Kim^1,2, Jooho Park⁶, Kwangmeyung Kim¹¹, Jun-Seob Kim^4,12,13*, Yoosoo Yang^5* and Man Kyu Shim^1,10*

¹Medicinal Materials Research Center, Biomedical Research Division, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea;
²KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, Republic of Korea;
³Department of Immunology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea;
⁴Department of Nano-Bioengineering, Incheon National University, Incheon, Republic of Korea;
⁵Department of Integrative Biotechnology, Sungkyunkwan University, Suwon, Republic of Korea;
⁶Department of Applied Life Science, BK21 Program, Konkuk University, Chungju, Republic of Korea;
⁷College of Pharmacy, Graduate School of Pharmaceutical Sciences, Kyung Hee University, Seoul, Republic of Korea;
⁸Department of Regulatory Science, Graduate School, Kyung Hee University, Seoul, Republic of Korea;
⁹Institute of Regulatory Innovation through Science (IRIS), Kyung Hee University, Seoul, Republic of Korea;
¹⁰Division of Bio-Medical Science and Technology, KIST School, University of Science and Technology, Seoul, Republic of Korea;
¹¹College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, Republic of Korea;
¹²Center for Brain-Machine Interface, Incheon National University, Incheon, Republic of Korea and
¹³Institute for New Drug Development, College of Life Science and Bioengineering, Incheon National University, Incheon, Republic of Korea

Correspondence: Jun-Seob Kim or Yoosoo Yang or Man Kyu Shim
These authors contributed equally: Yeongji Jang, Byeongmin Park, Jiwoong Choi

Abstract

Despite compelling evidence that tumor-derived extracellular vesicles (TEVs) exhibit either pro- or antitumorigenic phenotypes, pharmacological efforts have focused primarily on their indiscriminate suppression. Here, we propose a strategy of “switching TEVs off and on” to redirect them toward an immunogenic phenotype. Designed as a nanoproteolysis-targeting chimera (Nano-PROTAC) for TEV reprogramming, EVOTAC is composed of tripartite building blocks that integrate a PROTAC and a photosensitizer via a cancer biomarker-responsive cleavable linker and spontaneously self-assemble into supramolecular nanostructures. Upon biomarker-guided activation preferentially in tumors over normal tissues, EVOTAC initially eliminates TEVs by selectively degrading intracellular proteins involved in extracellular vesicle (EV) biogenesis. Subsequent localized laser irradiation reactivates EV generation, prompting tumor cells to predominantly produce immunogenic TEVs in response to photodynamic therapy (PDT). TEVs generated through this switching-off-and-on strategy independently exert pleiotropic effects by inhibiting tumor growth, migration, and metastasis while increasing mature dendritic cells and cytotoxic T lymphocytes in lymphoid organs and tumor tissues. This TEV-toggling process, therefore, significantly enhances both innate and adaptive immune responses to photoimmunotherapy, which leads to a complete regression of triple-negative breast cancer (TNBC) and prevents metastasis and recurrence. Our study highlights the potential of this therapeutic approach for precise TEV modulation and encourages further exploration, adding new breadth to the growing list of EV-targeting cancer immunotherapy concepts.

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