Niu Qiang, Liu Yu, Zheng Yujing, Tang Ziwei, Qian Yuna, Qi Ruogu, Shen Jianliang, Zhao Ping
School of Chemistry and Chemical Engineering, Guangdong Pharmaceutical University, Guangzhou 510006, China.
State Key Laboratory of Ophthalmology, Optometry and Vision Science, School of Ophthalmology and Optometry, School of Biomedical Engineering, Wenzhou Medical University, Wenzhou 325027, China.
Acta Pharm Sin B. 2022 Dec;12(12):4458-4471. doi: 10.1016/j.apsb.2022.11.002. Epub 2022 Nov 4.
Pyroptosis provides a new window for relieving the tumor immunosuppressive microenvironment (TIM) and promoting systemic immune responses for tumor treatments. However, gasdermin D (GSDMD), a key protein in the pyroptosis process mediated by caspase-1, is low expressed in the majority of tumor cells and small-molecule inhibitors of DNA methylation suffer from nonspecific or single-function defects. To address these issues, hexahistidine (His)-metal assembly (HmA) was employed as the drug delivery vector to load nigericin (Nig) and decitabine (DAC) affording a dual-drug delivery system (Nig + DAC)@HmA. The (Nig + DAC)@HmA nanoparticles are efficiently internalized by cells through endocytosis, easily escape from the lysosome, and are highly distributed in the tumor sites. DAC up-regulates the expression of GSDMD which is then cleaved by the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome and caspase-1 protein activated by Nig. Effective cancer cell pyroptosis is thus achieved and induces a significant systemic antitumor immunity for impressive tumor suppression with negligible side effects . Our results suggest that such an easy-to-manipulate self-assembled nano-system (Nig + DAC)@HmA provides a new anticancer path by enhancing pyroptosis through reinforced inflammation.
细胞焦亡为缓解肿瘤免疫抑制微环境（TIM）和促进肿瘤治疗的全身免疫反应提供了一个新窗口。然而，gasdermin D（GSDMD）作为caspase-1介导的细胞焦亡过程中的关键蛋白，在大多数肿瘤细胞中低表达，且DNA甲基化小分子抑制剂存在非特异性或单功能缺陷。为了解决这些问题，采用六组氨酸（His）-金属组装体（HmA）作为药物递送载体，负载尼日利亚菌素（Nig）和地西他滨（DAC），构建了一种双药递送系统（Nig + DAC）@HmA。（Nig + DAC）@HmA纳米颗粒通过内吞作用被细胞有效内化，易于从溶酶体中逃逸，并在肿瘤部位高度分布。DAC上调GSDMD的表达，然后被Nig激活的核苷酸结合寡聚化结构域样受体蛋白3（NLRP3）炎性小体和caspase-1蛋白切割。从而实现有效的癌细胞焦亡，并诱导显著的全身抗肿瘤免疫，以实现令人印象深刻的肿瘤抑制，且副作用可忽略不计。我们的结果表明，这种易于操作的自组装纳米系统（Nig + DAC）@HmA通过增强炎症来增强细胞焦亡，提供了一条新的抗癌途径。
