Zhang Ruixia, Zhang Yongjie, Hao Fei, Su Zhengxing, Duan Xing, Song Xiangrong
Department of Critical Care Medicine, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, No. 37, Guoxue Alley, Wuhou District, Chengdu, 610041, Sichuan Province, People's Republic of China.
Clinical Pharmacokinetics Laboratory, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, People's Republic of China.
Apoptosis. 2025 Jun 9. doi: 10.1007/s10495-025-02131-y.
Pancreatic cancer (PC) is one of the most common malignant tumors of the digestive tract. Gemcitabine (GEM) is a first-line chemotherapeutic agent for unresectable PC, but systemic distribution of the drug, drug resistance, and clinical side effects undermine its efficacy. This study utilized bone marrow mesenchymal stem cell-derived exosomes (BMSC-EXOs) as a delivery vehicle for a triple-drug combination (galectin-9 siRNA/DOGEM/indocyanine green) to improve synergistic therapy against PC. Galectin-9 siRNA, prodrug DOGEM, and ICG were loaded into BMSC-Exos by electroporation and vortexing to prepare nanoformulations (iEXO-DG-ICG). iEXO-DG-ICG had an average size of 132 ± 2.6 nm and its release rate in pH 6.0 medium was all faster than in pH 7.4 medium. The cytotoxicity of iEXO-DG-ICG against PANC-02 cells was stronger than free GEM both in vitro and in vivo. The protein expression of galectin-9 in tumor cells decreased by 79% after treatment with iEXO-DG-ICG, and the proportions of CD8⁺ T cells and IFN-γ⁺ CD8⁺ T cells increased while the proportions of Tregs decreased. The tumor inhibition rate of iEXO-DG-ICG was 90.3%. The present study successfully constructed a multimodal delivery system, designated iEXO-DG-ICG, using EXO derived from BM-MSCs as carriers. This system exhibited good tumor targeting and pH-responsive release characteristics. Both in vitro and in vivo studies confirmed that iEXO-DG-ICG significantly enhanced anti-tumor effects through the synergistic effect of chemotherapy, immunotherapy, and phototherapy. These findings provide a new strategy and a research foundation for the clinical treatment of pancreatic cancer.
胰腺癌（PC）是消化道最常见的恶性肿瘤之一。吉西他滨（GEM）是不可切除胰腺癌的一线化疗药物，但药物的全身分布、耐药性和临床副作用削弱了其疗效。本研究利用骨髓间充质干细胞来源的外泌体（BMSC-EXOs）作为三联药物组合（半乳糖凝集素-9 siRNA/DOGEM/吲哚菁绿）的递送载体，以改善对胰腺癌的协同治疗。通过电穿孔和涡旋将半乳糖凝集素-9 siRNA、前药DOGEM和ICG加载到BMSC-Exos中，制备纳米制剂（iEXO-DG-ICG）。iEXO-DG-ICG平均粒径为132±2.6 nm，其在pH 6.0培养基中的释放速率均快于pH 7.4培养基。iEXO-DG-ICG对PANC-02细胞的细胞毒性在体外和体内均强于游离吉西他滨。用iEXO-DG-ICG处理后，肿瘤细胞中半乳糖凝集素-9的蛋白表达下降了79%，CD8⁺T细胞和IFN-γ⁺CD8⁺T细胞的比例增加，而调节性T细胞的比例下降。iEXO-DG-ICG的肿瘤抑制率为90.3%。本研究成功构建了一种以BM-MSCs来源的EXO为载体的多模态递送系统，命名为iEXO-DG-ICG。该系统具有良好的肿瘤靶向性和pH响应释放特性。体外和体内研究均证实，iEXO-DG-ICG通过化疗、免疫治疗和光疗的协同作用显著增强了抗肿瘤效果。这些发现为胰腺癌的临床治疗提供了新的策略和研究基础。
