期刊
SMALL
卷 -, 期 -, 页码 -出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/smll.202305923
关键词
cancer therapy; gene regulation; mitochondria-targeting; mitochondrial metabolism; nanoparticles (NPs)
A mitochondria-targeted RNAi nanoparticle platform for effective regulation of mitochondrial metabolism and breast cancer therapy is developed. This platform can specifically deliver siRNA into the mitochondria and efficiently down-regulate mtDNA-encoded ATP6 expression, leading to combinatorial inhibition of tumor growth by suppressing the energy supply for tumor cells and repolarizing tumor-associated macrophages into tumor-inhibiting M1-like macrophages.
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. A mitochondria-targeted RNAi nanoparticle (NP) platform for effective regulation of mitochondrial metabolism and breast cancer (BCa) therapy is developed. This nanoplatform can specifically deliver siRNA into the mitochondria and efficiently down-regulate mtDNA-encoded ATP6 expression, leading to combinatorial inhibition of tumor growth via suppressing the energy supply for tumor cells and repolarizing tumor-associated macrophages (TAMs) into tumor-inhibiting M1-like macrophages.image
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