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Adv. Funct. Mater., Volume35, Issue25 June 19, 2025 2418138 | https://doi.org/10.1002/adfm.202418138 Engineered Cell-Derived Nanovesicles with CAR and PH20 for Enhanced Targeted Photodynamic Cancer Therapy and Tumor Microenvironment Modulation

Hyeon-Ji Oh¹, Gwang Yeol Park², Jieun Han¹, Boram Son^2,3, Jun-Hyeok Han¹, Hyomin Choi², Chun Gwon Park⁴, Dong Wook Choi⁵, Sung-Soo Park⁶, Wooram Park^1,7, Hee Ho Park^2,5,8

¹Department of Integrative Biotechnology, College of Biotechnology and Bioengineering, Sungkyunkwan University (SKKU), 2066, Seobu-ro, Jangan-gu, Suwon, Gyeonggi, 16419 Republic of Korea
²Department of Bioengineering, College of Engineering, Hanyang University, 222, Wangsimni-ro, Seongdong-gu, Seoul, 04763 Republic of Korea
³Department of Bio and Fermentation Convergence Technology, Kookmin University, 77, Jeongneung-ro, Seongbuk-gu, Seoul, 02707 Republic of Korea
⁴Department of Biomedical Engineering, Institute for Cross-disciplinary Studies (ICS), SKKU, 2066, Seobu-ro, Jangan-gu, Suwon, Gyeonggi, 16419 Republic of Korea
⁵Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, 145, Anam-ro, Seongbuk-gu, Seoul, 02841 Republic of Korea
⁶Biodrone Research Institute, Mdimune Inc., 49, Achasan-ro, Seongdong-gu, Seoul, 04790 Republic of Korea
⁷Department of MetaBioHealth, ICS, SKKU, 2066, Seobu-ro, Jangan-gu, Suwon, Gyeonggi, 16419 Republic of Korea
⁸SIMPLE Planet Inc., 48, Achasan-ro 17-gil, Seongdong-gu, Seoul, 04799 Republic of Korea

H.-J.O. and G.Y.P. contributed equally to this work
Corresponding Authors: Wooram Park, Hee Ho Park

Abstract

Photodynamic therapy (PDT) is a promising cancer treatment, but its clinical use is limited by nontargeted photosensitizers (PS) that accumulate in normal tissues, causing adverse effects, and poor penetration in tumor tissues due to the dense extracellular matrix (ECM). Here an innovative approach is presented using cell-derived nanovesicles (CNVs) engineered with chimeric antigen receptor (CAR) and hyaluronidase PH20 to enhance targeted PDT. The CAR–PH20 CNVs, loaded with the photosensitizer pheophorbide a (PheoA), specifically target HER2-expressing tumor cells and degrade hyaluronic acid in the tumor microenvironment (TME), improving tumor penetration and drug distribution. In vitro and in vivo experiments demonstrate increased reactive oxygen species (ROS) generation, improved tumor retention, and enhanced therapeutic efficacy compared to conventional methods. When combined with laser irradiation, these CNVs induce significant tumor cell apoptosis and inhibit tumor growth in mouse models, while minimizing toxicity to normal tissues. This platform offers a promising strategy for targeted, TME-modulating PDT with improved efficacy, and reduced side effects, marking a significant advance in nanodrug-based cancer therapies.

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