Activating Mitochondrial Complex I by Polyphenol Nanoparticle to Inhibit Hypoxia-Inducible Factor-1 Subunit α for Immunotherapy
Ruiling Xu, Mingda Zhao, Yuedi Yang, Xiaowen Han, Xiang Ren, Gongbing Liu, Hailong Wang, Jie Liang, Aiping Tong, Xingchen Peng, Yujiang Fan, Yong Sun
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.