Synthetically Lethal Biomimetic Nutri-hijacker Hitchhikes and Reprograms KRAS Mutation-Driven Metabolic Addictions for Pancreatic Ductal Adenocarcinoma Treatment.
Synthetically Lethal Biomimetic Nutri-hijacker Hitchhikes and Reprograms KRAS Mutation-Driven Metabolic Addictions for Pancreatic Ductal Adenocarcinoma Treatment.
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DOI：
10.1021/acsnano.3c04069
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发表时间：
2023-07
期刊：
影响因子：
17.1
通讯作者：
Yukun Huang;Yu Chen;Songlei Zhou;Laozhi Xie;K. Liang;Jianpei Xu;Qian Zhang;Huan Chen;Dayuan Wang;Qingxiang Song;Gan Jiang;Ni Mei;Fenfen Ma;Huiping Lu;Xiaoling Gao;Jun Chen
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作者：
Yukun Huang;Yu Chen;Songlei Zhou;Laozhi Xie;K. Liang;Jianpei Xu;Qian Zhang;Huan Chen;Dayuan Wang;Qingxiang Song;Gan Jiang;Ni Mei;Fenfen Ma;Huiping Lu;Xiaoling Gao;Jun Chen
靶向KRAS中功能获得性突变驱动的代谢成瘾的代谢疗法有希望通过选择性杀死恶性细胞而不伤害健康细胞来对抗癌症。然而，代谢补偿和异质性使目前的代谢治疗无效。在这里，我们提出了一个仿生“营养劫持者”与“特洛伊木马”的设计，诱导合成KRAS突变（mtKRAS）恶性细胞的致命性搭便车和重新编程的代谢成瘾。Nutri-hijacker由双胍修饰的纳米颗粒白蛋白和类黄酮组成，双胍修饰的纳米颗粒白蛋白损害糖酵解，类黄酮抑制mtKRAS恶性细胞对Nutri-hijacker的巨胞饮作用后的β-氨基分解。Nutri-hijacker抑制了mtKRAS恶性细胞的增殖和扩散，同时降低了肿瘤纤维化和免疫抑制。Nutri-hijacker在与临床试验失败的羟氯喹治疗相结合时，显着延长了胰腺导管腺癌（PDAC）荷瘤小鼠的寿命。总的来说，我们的研究结果表明，Nutri-hijacker是一种强大的KRAS突变定制抑制剂，基于mtKRAS驱动的代谢成瘾的合成致死性可能是对抗PDAC的一种有前途的策略。
Metabolic therapy targeting the metabolic addictions driven by gain-of-function mutations in KRAS is promising in fighting cancer through selective killing of malignant cells without hurting healthy cells. However, metabolic compensation and heterogeneity make current metabolic therapies ineffective. Here, we proposed a biomimetic "Nutri-hijacker" with "Trojan horse" design to induce synthetic lethality in KRAS-mutated (mtKRAS) malignant cells by hitchhiking and reprogramming the metabolic addictions. Nutri-hijacker consisted of the biguanide-modified nanoparticulate albumin that impaired glycolysis and a flavonoid that restrained glutaminolysis after the macropinocytosis of Nutri-hijacker by mtKRAS malignant cells. Nutri-hijacker suppressed the proliferation and spread of mtKRAS malignant cells while lowering tumor fibrosis and immunosuppression. Nutri-hijacker significantly extended the lifespan of pancreatic ductal adenocarcinoma (PDAC)-bearing mice when combined with the hydroxychloroquine-based therapies that failed in clinical trials. Collectively, our findings demonstrated that Nutri-hijacker is a strong KRAS mutation-customized inhibitor and the synthetic lethality based on mtKRAS-driven metabolic addictions might be a promising strategy against PDAC.