Gong Liangzhi, Chen Zhengsheng, Feng Kai, Luo Lei, Zhang Juntao, Yuan Ji, Ren Yajing, Wang Yang, Zheng Xianyou, Li Qing
Institute of Microsurgery on Extremities, Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China.
J Nanobiotechnology. 2024 Mar 11;22(1):105. doi: 10.1186/s12951-024-02361-3.
Chemotherapy is an important therapeutic approach for malignant tumors for it triggers apoptosis of cancer cells. However, chemotherapy also induces senescence of stromal cells in the tumor microenvironment to promote tumor progression. Strategies aimed at killing tumor cells while simultaneously eliminating senescent stromal cells represent an effective approach to cancer treatment. Here, we developed an engineered Src-siRNA delivery system based on small extracellular vesicles (sEVs) to simultaneously eliminate senescent stromal cells and tumor cells for cancer therapy. The DSPE-PEG-modified urokinase plasminogen activator (uPA) peptide was anchored to the membranes of induced mesenchymal stem cell-derived sEVs (uPA-sEVs), and Src siRNA was loaded into the uPA-sEVs by electroporation (uPA-sEVs-siSrc). The engineered uPA-sEVs-siSrc retained the basic sEVs properties and protected against siSrc degradation. uPA peptide modification enhanced the sEVs with the ability to simultaneously target doxorubicin-induced senescent stromal cells and tumor cells. Src silencing by uPA-sEVs-siSrc induced apoptosis of both senescent stromal cells and tumor cells. The uPA-sEVs-siSrc displayed preferential tumor accumulation and effectively inhibited tumor growth in a tumor xenograft model. Furthermore, uPA-sEVs-siSrc in combination with doxorubicin significantly reduced the senescence burden and enhanced the therapeutic efficacy of chemotherapy. Taken together, uPA-sEVs-siSrc may serve as a promising therapy to kill two birds with one stone, not only killing tumor cells to achieve remarkable antitumor effect, but also eliminating senescent cells to enhance the efficacy of chemotherapeutic agent in tumor regression.
化疗是恶性肿瘤的一种重要治疗方法，因为它能引发癌细胞凋亡。然而，化疗也会诱导肿瘤微环境中基质细胞衰老，从而促进肿瘤进展。旨在杀死肿瘤细胞同时消除衰老基质细胞的策略是一种有效的癌症治疗方法。在此，我们开发了一种基于小细胞外囊泡（sEVs）的工程化Src-siRNA递送系统，用于同时消除衰老基质细胞和肿瘤细胞以进行癌症治疗。将DSPE-PEG修饰的尿激酶型纤溶酶原激活剂（uPA）肽锚定到诱导的间充质干细胞衍生的sEVs（uPA-sEVs）膜上，并通过电穿孔将Src siRNA加载到uPA-sEVs中（uPA-sEVs-siSrc）。工程化的uPA-sEVs-siSrc保留了基本的sEVs特性，并能防止siSrc降解。uPA肽修饰增强了sEVs同时靶向阿霉素诱导的衰老基质细胞和肿瘤细胞的能力。uPA-sEVs-siSrc介导的Src沉默诱导衰老基质细胞和肿瘤细胞凋亡。uPA-sEVs-siSrc在肿瘤异种移植模型中表现出优先的肿瘤蓄积，并有效抑制肿瘤生长。此外，uPA-sEVs-siSrc与阿霉素联合使用可显著减轻衰老负担，并增强化疗的治疗效果。综上所述，uPA-sEVs-siSrc可能是一种很有前景的一石二鸟的疗法，不仅能杀死肿瘤细胞以取得显著的抗肿瘤效果，还能消除衰老细胞以增强化疗药物在肿瘤消退中的疗效。
