新的证据表明线粒体代谢功能障碍对促进癌症的发生和进展具有重要作用。线粒体基因组（mtDNA）编码蛋白的异常表达广泛涉及线粒体代谢功能障碍，对其表达的靶向调控可能是癌症治疗的有效策略，但由于线粒体双膜的保护而受到挑战。在此，开发了一种针对线粒体的 RNAi 纳米颗粒（NP）平台，用于有效调节线粒体代谢和乳腺癌（BCa）治疗。该纳米平台由亲水性聚乙二醇（PEG）外壳、疏水性聚（2-（二异丙氨基）乙基甲基丙烯酸酯）（PDPA）核心以及线粒体靶向和膜穿透肽两亲物（MMPA）和电荷介导的复合物组成。嵌入核心的小干扰RNA (siRNA)。在肿瘤积累和被肿瘤细胞内化后，这些 NP 可以对内体 pH 做出反应，暴露 MMPA/siRNA 复合物，该复合物可以特异性地将 siRNA 转运到线粒体中，从而下调 mtDNA 编码的蛋白表达（例如 ATP6 和 CYB）。更重要的是，由于 ATP6 下调可以抑制 ATP 产生并增强活性氧 (ROS) 产生，从而诱导线粒体损伤和 mtDNA 渗漏到肿瘤组织中，因此 NP 可以通过抑制 ATP 产生和复极肿瘤相关巨噬细胞来组合抑制肿瘤生长。 TAM）通过 mtDNA 转化为肿瘤抑制性 M1 样巨噬细胞。© 2023 Wiley-VCH GmbH。

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.