肿瘤细胞治疗研究
英文原题：Biomimetic Macrophage Membrane-Camouflaged Nanoparticles Induce Ferroptosis by Promoting Mitochondrial Damage in Glioblastoma.
对铁死亡日益深入的理解已表明其在癌症中的作用和治疗潜力；然而，这些认识尚未转化为有效的疗法。
对铁死亡理解的不断深入已表明其在癌症中的作用和治疗潜力；然而，这些认识尚未转化为有效的疗法。胶质母细胞瘤（GBM）患者面临黯淡的预后，并因可用治疗选择有限而遭遇重重挑战。在本研究中，我们在铁死亡诱导剂（RSL3）存在的情况下进行了全基因组CRISPR-Cas9筛选，以鉴定参与铁死亡的关键驱动基因。我们鉴定出ALOX15，一种关键的脂氧合酶（LOX），是铁死亡的重要驱动因子。使用小激活RNA（saRNA）介导ALOX15的表达，促进了GBM细胞中的铁死亡。随后，我们将负载saALOX15的介孔聚多巴胺（MPDA）包被以Angiopep-2修饰的巨噬细胞膜（MMs），以减少单核吞噬细胞系统（MPS）的清除，并增强该复合物在原位GBM特异性靶向治疗中穿越血脑屏障（BBB）的能力。这些生成的杂合纳米颗粒（NPs）通过介导线粒体功能障碍并使线粒体形态异常来诱导铁死亡。在体内，修饰后的MM使NPs能够靶向GBM细胞，对GBM进展发挥显著的抑制作用，并促进GBM的放射敏感性。我们的结果揭示了ALOX15是GBM中一个有前景的治疗靶点，并提出了一种依赖于MMs生物学特性的仿生策略，以增强NPs在治疗GBM中的体内性能。
The increasing understanding of ferroptosis has indicated its role and therapeutic potential in cancer; however, this knowledge has yet to be translated into effective therapies. Glioblastoma (GBM) patients face a bleak prognosis and encounter challenges due to the limited treatment options available. In this study, we conducted a genome-wide CRISPR-Cas9 screening in the presence of a ferroptosis inducer (RSL3) to identify the key driver genes involved in ferroptosis. We identified ALOX15, a key lipoxygenase (LOX), as an essential driver of ferroptosis. Small activating RNA (saRNA) was used to mediate the expression of ALOX15 promoted ferroptosis in GBM cells. We then coated saALOX15-loaded mesoporous polydopamine (MPDA) with Angiopep-2-modified macrophage membranes (MMs) to reduce the clearance by the mononuclear phagocyte system (MPS) and increase the ability of the complex to cross the blood-brain barrier (BBB) during specific targeted therapy of orthotopic GBM. These generated hybrid nanoparticles (NPs) induced ferroptosis by mediating mitochondrial dysfunction and rendering mitochondrial morphology abnormal. In vivo, the modified MM enabled the NPs to target GBM cells, exert a marked inhibitory effect on GBM progression, and promote GBM radiosensitivity. Our results reveal ALOX15 to be a promising therapeutic target in GBM and suggest a biomimetic strategy that depends on the biological properties of MMs to enhance the in vivo performance of NPs for treating GBM.
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