Jin Fangfang, Wei Xingyu, Liu Yongcan, Tang Lisha, Ren Jun, Yang Jing, Lin Can, Hu Jiayuan, Sun Minghui, Li Genyou, Yuan Zihao, Zhao Wen, Wang Xiaozhong, Yang Zesong, Zhang Ling
Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, College of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, China.
Jiangxi Province Key Laboratory of Immunology and Inflammation, Jiangxi Provincial Clinical Research Center for Laboratory Medicine, Department of Clinical Laboratory, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, China.
Biomaterials. 2025 Jun;317:123091. doi: 10.1016/j.biomaterials.2025.123091. Epub 2025 Jan 3.
Acute myeloid leukemia (AML) presents significant treatment challenges due to the severe toxicities and limited efficacy of conventional therapies, highlighting the urgency for innovative approaches. Organelle-targeting therapies offer a promising avenue to enhance therapeutic outcomes while minimizing adverse effects. Herein, inspired that primary AML cells are enriched with lysosomes and sensitive to lysosomophilic drugs (e.g., LLOMe), we developed a smart nanodrug (Cas-CMV@LM) including the engineered cell membrane vesicles (CMVs) nanocarrier and the encapsulated drug cargo LLOMe (LM). Briefly, the nanodrug with organ-cell-organelle cascade-targeting function could firstly home to the bone marrow guided by CMVs derived from CXCR4-overexpressing bone marrow mesenchymal stem cells (BMSC), subsequently target leukemia cells via CD33 and CD123 aptamers anchored on the vesicles, eventually precisely attack the lysosomes of leukemia cells. Consequently, Cas-CMV@LM specifically inhibited leukemia cell proliferation and triggered necroptosis in vitro. Importantly, the cascade-targeting nanodrug displayed high biosafety and significantly impeded leukemia progression in AML patient-derived xenograft (PDX) model. Collectively, this study provides a paradigm for precision leukemia treatment from the perspective of targeting organelle-lysosome.
急性髓系白血病（AML）由于传统疗法的严重毒性和有限疗效而面临重大治疗挑战，凸显了创新方法的紧迫性。细胞器靶向疗法为提高治疗效果同时将副作用降至最低提供了一条有前景的途径。在此，受原发性AML细胞富含溶酶体且对亲溶酶体药物（如氯苯甲酰亮氨酸甲酯，LLOMe）敏感的启发，我们开发了一种智能纳米药物（Cas-CMV@LM），其包括工程化细胞膜囊泡（CMV）纳米载体和封装的药物LLOMe（LM）。简而言之，具有器官-细胞-细胞器级联靶向功能的纳米药物首先在源自过表达CXCR4的骨髓间充质干细胞（BMSC）的CMV引导下归巢至骨髓，随后通过锚定在囊泡上的CD33和CD123适体靶向白血病细胞，最终精确攻击白血病细胞的溶酶体。因此，Cas-CMV@LM在体外特异性抑制白血病细胞增殖并引发坏死性凋亡。重要的是，这种级联靶向纳米药物显示出高生物安全性，并在AML患者来源的异种移植（PDX）模型中显著阻碍白血病进展。总体而言，本研究从靶向细胞器-溶酶体的角度为精准白血病治疗提供了一个范例。
