Remodeling of Mitochondrial Metabolism by a Mitochondria-Targeted RNAi Nanoplatform for Effective Cancer Therapy.

Autor: Xu R; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, P. R. China.; Guangzhou Key Laboratory of Medical Nanomaterials, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, P. R. China.; Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-Sen Memorial Hospital, Foshan, 528200, P. R. China., Huang L; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, P. R. China.; Guangzhou Key Laboratory of Medical Nanomaterials, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, P. R. China.; Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-Sen Memorial Hospital, Foshan, 528200, P. R. China., Liu J; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, P. R. China.; Guangzhou Key Laboratory of Medical Nanomaterials, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, P. R. China.; Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-Sen Memorial Hospital, Foshan, 528200, P. R. China., Zhang Y; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, P. R. China.; Guangzhou Key Laboratory of Medical Nanomaterials, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, P. R. China.; Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-Sen Memorial Hospital, Foshan, 528200, P. R. China., Xu Y; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, P. R. China.; Guangzhou Key Laboratory of Medical Nanomaterials, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, P. R. China.; Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-Sen Memorial Hospital, Foshan, 528200, P. R. China., Li R; The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, P. R. China., Su S; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, P. R. China.; Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-Sen Memorial Hospital, Foshan, 528200, P. R. China., Xu X; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, P. R. China.; Guangzhou Key Laboratory of Medical Nanomaterials, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, P. R. China.; Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-Sen Memorial Hospital, Foshan, 528200, P. R. China.
Jazyk: angličtina
Zdroj: Small (Weinheim an der Bergstrasse, Germany) [Small] 2024 Mar; Vol. 20 (10), pp. e2305923. Date of Electronic Publication: 2023 Nov 02.
DOI: 10.1002/smll.202305923
Abstrakt: Emerging evidence has demonstrated the significant contribution of mitochondrial metabolism dysfunction to promote cancer development and progression. Aberrant expression of mitochondrial genome (mtDNA)-encoded proteins widely involves mitochondrial metabolism dysfunction, and targeted regulation of their expression can be an effective strategy for cancer therapy, which however is challenged due to the protection by the mitochondrial double membrane. Herein, a mitochondria-targeted RNAi nanoparticle (NP) platform for effective regulation of mitochondrial metabolism and breast cancer (BCa) therapy is developed. This nanoplatform is composed of a hydrophilic polyethylene glycol (PEG) shell, a hydrophobic poly(2-(diisopropylamino)ethyl methacrylate) (PDPA) core, and charged-mediated complexes of mitochondria-targeting and membrane-penetrating peptide amphiphile (MMPA) and small interfering RNA (siRNA) embedded in the core. After tumor accumulation and internalization by tumor cells, these NPs can respond to the endosomal pH to expose the MMPA/siRNA complexes, which can specifically transport siRNA into the mitochondria to down-regulate mtDNA-encoded protein expression (e.g., ATP6 and CYB). More importantly, because ATP6 down-regulation can suppress ATP production and enhance reactive oxygen species (ROS) generation to induce mitochondrial damage and mtDNA leakage into tumor tissues, the NPs can combinatorially inhibit tumor growth via suppressing ATP production and repolarizing tumor-associated macrophages (TAMs) into tumor-inhibiting M1-like macrophages by mtDNA.
(© 2023 Wiley-VCH GmbH.)
Databáze: MEDLINE
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