Advancing Tumor-Targeted Chemo-Immunotherapy: Development of the CAR-M-derived Exosome-Drug Conjugate

作者：Yunhan Jiang, Xiaoqiu Xu, Dongmei Fan, Pingxian Liu, Meng Zhou, Mengdi Cheng, Jiasheng Huang, Youfu Luo, Yingqiang Guo, Tao Yang · 发表于：Journal of Medicinal Chemistry · 年份：2024 · DOI：10.1021/acs.jmedchem.4c00753 · 被引用次数：20 · 研究领域：Extracellular vesicles in disease、CAR-T cell therapy research、RNA Interference and Gene Delivery

Traditional antibody-drug conjugates (ADCs) mainly suppress tumor growth through either chemotherapy with cytotoxic payloads or immunotherapy with immuno-modulators. However, a single therapeutic modality may limit their exploration. Herein, we developed a new type of drug conjugate termed CAR-EDC (CAR-M-derived exosome-drug conjugate) by using CAR-exosomes from CAR-M cells as the targeting drug carrier that contains a high level of CXCL10. CAR-exosomes could significantly enhance the immunological activation and migratory capacity of T lymphocytes and promote their differentiation into CD8+ T cells. It also increased the proportion of M1 macrophages. The CAR-EDC, covalently loaded with SN-38, was internalized into Raji cells through endocytosis mediated by the CAR molecules. It exerted excellent antitumor activity in vivo by virtue of not only chemotherapy by SN38 but also immunotherapy by CXCL10-mediated antitumor immunity. Generally, this study provides an exosome-drug conjugate system with enhanced antitumor effects over traditional ADCs through the synergism of chemotherapy and immunotherapy.