Yuan Zuowei, Jiang Guoyun, Yuan Ying, Liang Qian, Hou Yaxin, Zhang Wenyao, Tang Lujia, Fan Kelong, Feng Wenli
Department of Clinical Hematology, School of Laboratory Medicine, Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), Chongqing Medical University, Chongqing, 400016, China.
Department of Clinical Laboratory, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, 400021, China.
J Nanobiotechnology. 2025 Mar 28;23(1):252. doi: 10.1186/s12951-025-03335-9.
Tyrosine kinase inhibitors (TKIs) constitute the primary treatment for chronic myeloid leukemia (CML). However, resistance to TKIs often leads to treatment failure. Pyroptosis, a form of programmed cell death, has emerged as a promising strategy in cancer therapy due to its ability to eliminate tumor cells while stimulating antitumor immunity. Low-dose decitabine (DAC) has been shown to reverse methylation-induced silencing of the pyroptosis-related gene gasdermin E (GSDME) in some tumor cells, offering a potential new therapeutic option for CML. Herein, we propose a combination therapy using 5-fluorouracil (5-FU), a broad-spectrum chemotherapeutic agent, and low-dose DAC to induce pyroptosis in CML cells via the caspase-3/GSDME pathway. However, the nonspecific targeting of 5-FU diminishes its pyroptosis efficacy and causes off-target toxicity, highlighting the need for a targeted drug delivery system.
In this study, we developed 5-FU@HFn nanoparticles (NPs) by loading 5-FU into the recombinant human heavy chain ferritin (HFn) nanocage through a high-temperature via the drug channels on the protein cage. The loading efficiency was approximately 50.62 ± 1.17 µg of 5-FU per mg of HFn. 5-FU@HFn NPs selectively targeted CML cells through CD71-mediated uptake, significantly enhancing the therapeutic effects of 5-FU. When combined with DAC, 5-FU@HFn NPs effectively activated pyroptosis via the caspase-3/GSDME pathway in both TKI-sensitive and TKI-resistant CML cells. In a CML mouse model, this combination therapy significantly suppressed tumorigenesis and triggered a robust antitumor immune response, facilitating the clearance of leukemic cells. Furthermore, the 5-FU@HFn NPs exhibited excellent in vivo safety.
The innovative therapeutic strategy, combining 5-FU@HFn nanoparticles with low-dose DAC, effectively induces caspase-3/GSDME-mediated pyroptosis and activates antitumor immunity for CML. This approach offers a potential alternative for patients resistant or intolerant to TKIs.
酪氨酸激酶抑制剂（TKIs）是慢性髓性白血病（CML）的主要治疗方法。然而，对TKIs的耐药性常常导致治疗失败。细胞焦亡是一种程序性细胞死亡形式，因其能够在刺激抗肿瘤免疫的同时消除肿瘤细胞，已成为癌症治疗中有前景的策略。低剂量地西他滨（DAC）已被证明可在一些肿瘤细胞中逆转甲基化诱导的细胞焦亡相关基因gasdermin E（GSDME）的沉默，为CML提供了一种潜在的新治疗选择。在此，我们提出一种联合疗法，使用广谱化疗药物5-氟尿嘧啶（5-FU）和低剂量DAC，通过半胱天冬酶-3/GSDME途径诱导CML细胞发生细胞焦亡。然而，5-FU的非特异性靶向降低了其细胞焦亡疗效并导致脱靶毒性，凸显了靶向药物递送系统的必要性。
在本研究中，我们通过高温将5-FU通过蛋白笼上的药物通道加载到重组人重链铁蛋白（HFn）纳米笼中，制备了5-FU@HFn纳米颗粒（NPs）。负载效率约为每毫克HFn负载50.62±1.17μg的5-FU。5-FU@HFn NPs通过CD71介导的摄取选择性靶向CML细胞，显著增强了5-FU的治疗效果。当与DAC联合使用时，5-FU@HFn NPs在TKI敏感和TKI耐药的CML细胞中均通过半胱天冬酶-3/GSDME途径有效激活细胞焦亡。在CML小鼠模型中，这种联合疗法显著抑制肿瘤发生并引发强烈的抗肿瘤免疫反应，促进白血病细胞的清除。此外，5-FU@HFn NPs表现出优异的体内安全性。
将5-FU@HFn纳米颗粒与低剂量DAC相结合的创新治疗策略，有效诱导半胱天冬酶-3/GSDME介导的细胞焦亡并激活CML的抗肿瘤免疫。这种方法为对TKIs耐药或不耐受的患者提供了一种潜在的替代方案。
