A Multifunctional Exosome with Dual Homeostasis Disruption Augments cGAS-STING-Mediated Tumor Immunotherapy by Boosting Ferroptosis

IF 9.6 1区 材料科学 Q1 CHEMISTRY, MULTIDISCIPLINARY Nano Letters Pub Date : 2024-10-30 DOI:10.1021/acs.nanolett.4c03862
Xiaoqing Wei, Ling Sun, Junzhen Deng, Qingping Yang, Jingya Zhao, Shaobing Zhou
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Abstract

Ferroptosis has shown great potential in activating antitumor immunity. However, the cunning tumor cells can evade ferroptosis by increasing the efflux of iron and promoting the production of the reductant glutathione to mitigate oxidative stress. Herein, a multifunctional exosome loaded with manganese-doped iron oxide nanoparticles (MnIO), GW4869, and l-buthionine sulfoximine (BSO) is developed to disrupt the iron metabolism homeostasis and redox homeostasis to enhance tumor immunotherapy. The efficient transport of MnIO by exosomes and the inhibition of iron exocytosis by GW4869 led to a high retention of up to 29.57% ID/g for iron in the tumors. Such a high retention of iron, in combination with the BSO-induced disruption of the redox homeostasis, effectively promotes the ferroptosis of tumor cells. Consequently, the multifunctional exosomes that noticeably enhance ferroptosis by dual homeostasis disruption provoke the cGAS-STING-based antitumor immune response and effectively suppress tumor growth and lung metastasis in orthotopic breast cancer.

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一种具有双重稳态破坏功能的多功能外泌体通过促进铁突变增强了 cGAS-STING 介导的肿瘤免疫疗法
铁渗出在激活抗肿瘤免疫方面显示出巨大的潜力。然而,狡猾的肿瘤细胞可以通过增加铁的外流和促进还原剂谷胱甘肽的产生来缓解氧化应激,从而逃避铁跃迁。在此,我们开发了一种装载掺锰氧化铁纳米颗粒(MnIO)、GW4869和l-丁硫磺酰亚胺(BSO)的多功能外泌体,以破坏铁代谢平衡和氧化还原平衡,从而增强肿瘤免疫疗法。外泌体可高效转运 MnIO,而 GW4869 可抑制铁的外泌,因此铁在肿瘤中的保留率高达 29.57% ID/g。如此高的铁滞留率与 BSO 诱导的氧化还原平衡破坏相结合,有效地促进了肿瘤细胞的铁突变。因此,多功能外泌体通过双重稳态破坏明显增强了铁的嗜酸性,激起了基于cGAS-STING的抗肿瘤免疫反应,并有效抑制了正位乳腺癌的肿瘤生长和肺转移。
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来源期刊
Nano Letters
Nano Letters 工程技术-材料科学:综合
CiteScore
16.80
自引率
2.80%
发文量
1182
审稿时长
1.4 months
期刊介绍: Nano Letters serves as a dynamic platform for promptly disseminating original results in fundamental, applied, and emerging research across all facets of nanoscience and nanotechnology. A pivotal criterion for inclusion within Nano Letters is the convergence of at least two different areas or disciplines, ensuring a rich interdisciplinary scope. The journal is dedicated to fostering exploration in diverse areas, including: - Experimental and theoretical findings on physical, chemical, and biological phenomena at the nanoscale - Synthesis, characterization, and processing of organic, inorganic, polymer, and hybrid nanomaterials through physical, chemical, and biological methodologies - Modeling and simulation of synthetic, assembly, and interaction processes - Realization of integrated nanostructures and nano-engineered devices exhibiting advanced performance - Applications of nanoscale materials in living and environmental systems Nano Letters is committed to advancing and showcasing groundbreaking research that intersects various domains, fostering innovation and collaboration in the ever-evolving field of nanoscience and nanotechnology.
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