State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an 710032, China.
Department of Neurosurgery, Xijing Hospital, Xi'an 710032, China.
ACS Nano. 2023 Dec 12;17(23):23746-23760. doi: 10.1021/acsnano.3c07555. Epub 2023 Nov 22.
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.
对铁死亡的认识不断深入，表明其在癌症中的作用和治疗潜力；然而，这方面的知识尚未转化为有效的治疗方法。胶质母细胞瘤（GBM）患者预后不佳，由于治疗选择有限，面临诸多挑战。在这项研究中，我们在铁死亡诱导剂（RSL3）存在的情况下，对全基因组 CRISPR-Cas9 进行了筛选，以确定涉及铁死亡的关键驱动基因。我们确定 ALOX15，一种关键的脂氧合酶（LOX），是铁死亡的关键驱动因素。小激活 RNA（saRNA）被用于介导 ALOX15 的表达，促进 GBM 细胞发生铁死亡。然后，我们用载有 saALOX15 的介孔聚多巴胺（MPDA）包裹 Angiopep-2 修饰的巨噬细胞膜（MM），以减少单核吞噬细胞系统（MPS）的清除，并增加复合物在特定的原位 GBM 靶向治疗中穿过血脑屏障（BBB）的能力。这些生成的杂化纳米颗粒（NPs）通过介导线粒体功能障碍和使线粒体形态异常来诱导铁死亡。在体内，修饰的 MM 使 NPs 能够靶向 GBM 细胞，对 GBM 进展产生显著抑制作用，并促进 GBM 对放疗的敏感性。我们的研究结果表明 ALOX15 是 GBM 有前途的治疗靶点，并提出了一种仿生策略，该策略依赖于 MM 的生物学特性来增强 NPs 治疗 GBM 的体内性能。
