Activating Mitochondrial Complex I by Polyphenol Nanoparticle to Inhibit Hypoxia-Inducible Factor-1 Subunit α for Immunotherapy.

IF 15.8 1区 材料科学 Q1 CHEMISTRY, MULTIDISCIPLINARY
ACS Nano Pub Date : 2025-07-21 DOI:10.1021/acsnano.5c03547
Ruiling Xu,Mingda Zhao,Yuedi Yang,Xiaowen Han,Xiang Ren,Gongbing Liu,Hailong Wang,Jie Liang,Aiping Tong,Xingchen Peng,Yujiang Fan,Yong Sun
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引用次数: 0

Abstract

Mitochondrial respiratory dysfunction accelerates the conversion of cellular oxidative phosphorylation into malignancy-dependent glycolysis to enhance tumor immune escape. Here, engineering PEGylated epigallocatechin gallate nanoparticles (PE-NPs) in injectable hyaluronan gels upregulated oxidative phosphorylation by activating mitochondrial complex I of B16F10 cells, which greatly increased NAD+ level, a NADH oxidation product catalyzed by complex I, to inhibit hypoxia-inducible factor-1 expression. The immunomodulatory effect of PE-NPs was confirmed by the simultaneous downregulation of the MAPK, PI3K-AKT/mTOR pathways, and PD-L1 protein expression. Surgical resection, paraneoplastic administration, and distal metastasis models confirmed that PE-NPs significantly suppressed tumor recurrence, growth, and metastasis. It also promoted a systemic immune response by increasing CD8+ T cell differentiation, reducing CD4+ regulatory T cells in melanoma, promoting splenic dendritic cell maturation, and improving memory T cell differentiation. A synergistic approach using PE-NPs with PD-1/PD-L1 inhibitors significantly enhanced immune efficacy, confirming the feasibility of activating mitochondrial complex I boosts oxidative phosphorylation to potentiate melanoma immunotherapy as an effective strategy.
多酚纳米颗粒激活线粒体复合体I抑制缺氧诱导因子-1亚单位α的免疫治疗。
线粒体呼吸功能障碍加速细胞氧化磷酸化转化为恶性依赖的糖酵解,从而增强肿瘤免疫逃逸。本研究通过在注射透明质酸凝胶中修饰聚乙二醇化的表没食子儿茶素没食子酸酯纳米颗粒(PE-NPs),通过激活B16F10细胞线粒体复合体I来上调氧化磷酸化,从而大大提高复合体I催化的NADH氧化产物NAD+水平,从而抑制缺氧诱导因子-1的表达。PE-NPs的免疫调节作用通过同时下调MAPK、PI3K-AKT/mTOR通路和PD-L1蛋白表达得到证实。手术切除、副肿瘤给药和远端转移模型证实PE-NPs显著抑制肿瘤复发、生长和转移。它还通过增加CD8+ T细胞分化、减少黑色素瘤中CD4+调节性T细胞、促进脾树突状细胞成熟和改善记忆性T细胞分化来促进全身免疫反应。使用PE-NPs与PD-1/PD-L1抑制剂的协同方法显着提高了免疫疗效,证实了激活线粒体复合体I促进氧化磷酸化以增强黑色素瘤免疫治疗作为有效策略的可行性。
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来源期刊
ACS Nano
ACS Nano 工程技术-材料科学:综合
CiteScore
26.00
自引率
4.10%
发文量
1627
审稿时长
1.7 months
期刊介绍: ACS Nano, published monthly, serves as an international forum for comprehensive articles on nanoscience and nanotechnology research at the intersections of chemistry, biology, materials science, physics, and engineering. The journal fosters communication among scientists in these communities, facilitating collaboration, new research opportunities, and advancements through discoveries. ACS Nano covers synthesis, assembly, characterization, theory, and simulation of nanostructures, nanobiotechnology, nanofabrication, methods and tools for nanoscience and nanotechnology, and self- and directed-assembly. Alongside original research articles, it offers thorough reviews, perspectives on cutting-edge research, and discussions envisioning the future of nanoscience and nanotechnology.
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