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조회102

한양대학교

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J. Control. Release, Feb 22 2025, S0168-3659(25)00178-6 | https://doi.org/10.1016/j.jconrel.2025.02.065 Dual-delivery of exosome inhibitor and immune-activating gene via lipid nano-assemblies for tumor immune evasion inhibition

Jaehyun Kim ^a,b,1, Minjeong Kim ^a,1, Heesoo Han^a, SangJin Kim ^a, Shayan Fakhraei Lahiji ^a,b, Yong-Hee Kim ^a,b,c

^aDepartment of Bioengineering, Institute for Bioengineering and Biopharmaceutical Research, Hanyang University, 04763 Seoul, Republic of Korea
^bCursus Bio Inc. Icure Tower, Gangnam-gu, Seoul 06170, Republic of Korea
^cInstitute for Bioengineering and Biopharmaceutical Research (IBBR), Hanyang University, 04763 Seoul, Republic of Korea

¹These authors contributed equally to this work.
Corresponding author: Yong-Hee Kim

Abstract

The tumor microenvironment, with its complex immune evasion mechanisms, significantly hinders the efficacy of anti-tumor immunotherapies, including immune checkpoint inhibitors. Consequently, there is a strong impetus for extensive research to elucidate the immunosuppressive mechanisms within the tumor microenvironment and to develop novel therapeutic strategies. In this study, we have developed a drug/gene delivery system (folate-modified GW4869-loaded siIRF3 nano-complex, FD9R-GW/siIRF3) designed to simultaneously target and inhibit two key immune evasion pathways in the tumor microenvironment. The folate receptor-mediated delivery of GW4869 to cancer cells and tumor-associated macrophages (TAMs) led to the suppression of biosynthesis and release of tumor-derived exosomes (TEXs) containing exosomal PD-L1. Furthermore, IRF3 gene silencing effectively inhibited the M2-type differentiation of TAMs, and suppressed the secretion of CC motif chemokine ligand 22 (CCL22) in cancer cells, consequently reducing the recruitment of regulatory T cells (Tregs). The efficacy of FD9R-GW/siIRF3 in impeding tumor immune evasion was substantiated by an augmented recruitment of cytotoxic T cells and a diminished M2 macrophage polarization in the folate receptor-expressing 4 T1 allograft breast cancer model. Furthermore, the combination of a-PD-1 immunotherapy with FD9R-GW/siIRF3 led to a significant enhancement in the antitumor immune response, as evidenced by the inhibition of circulating tumor-derived exosomal PD-L1.

논문정보

형식Research article
게재일2025년 02월 (BRIC 등록일 2025-02-25)
연구진국내 연구진
분야 생명과학 > 생물공학

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