Song Mingzhu, Yuan Jiayu, Zhang Ge, Sun Mengdi, Zhang Yifei, Su Xiangchen, Lv Ruizhen, Zhao Yuting, Shi Yijie, Zhao Liang
School of Pharmacy, Jinzhou Medical University, Jinzhou 121000, PR China.
School of Pharmacy, Jinzhou Medical University, Jinzhou 121000, PR China; Key Laboratory of Neurodegenerative Diseases of Liaoning Province, Jinzhou Medical University, Jinzhou, China; Collaborative Innovation Center for Age-related Disease, Jinzhou Medical University, Jinzhou, Liaoning, China.
Acta Biomater. 2025 Jan 24;193:514-530. doi: 10.1016/j.actbio.2024.12.027. Epub 2024 Dec 19.
Mitochondrial targeting in gliomas represents a novel therapeutic strategy with significant potential to enhance drug sensitivity by effectively killing glioma cells at the mitochondrial level. In this study, we developed artificial mitochondria derived from mitochondrial membrane-based nanovesicles, enabling precise mitochondrial targeting of doxorubicin (Dox) to selectively eradicate cancer cells by amplifying multiple cell death pathways. It was found that Dox-encapsulating mitochondria-based nanovesicles (DOX-MitoNVs) exhibited an extraordinary ability to penetrate the blood-brain barrier (BBB), specifically targeting gliomas. By targeting mitochondria instead of locating at the nucleus, DOX-MitoNVs not only amplified Dox mediated apoptosis effects through the overloading of intracellular Ca but also intensified ferroptosis by generating reactive oxygen species (ROS). Furthermore, DOX-MitoNVs demonstrated a significant ability to modulate the tumor immune microenvironment, thereby inducing pronounced immunogenic cell death (ICD) effects. In summary, it presents a novel therapeutic strategy utilizing DOX-MitoNVs for precise mitochondrial targeting in gliomas, enhancing drug sensitivity, inducing multiple cell death pathways, and modulating the tumor immune microenvironment to promote immunogenic cell death. STATEMENT OF SIGNIFICANCE: Mitochondrial targeting in gliomas is a promising therapeutic strategy that enhances drug sensitivity by exploiting glioma cells' mitochondrial vulnerabilities. We engineered mitochondrial membrane-based nanovesicles as artificial mitochondria for precise mitochondrial targeting of Dox. This approach facilitates selective cancer cell eradication and amplifies multiple cell death pathways alongside immunogenic chemotherapy. Notably, DOX-MitoNVs effectively cross the BBB and specifically target gliomas. By focusing on mitochondria, Dox induces apoptosis and intensifies ferroptosis through ROS generation. Additionally, DOX-MitoNVs can transform the tumor immune microenvironment, promoting ICD. Overall, DOX-MitoNVs offer a promising platform for enhanced glioma therapy.
胶质瘤中的线粒体靶向是一种具有巨大潜力的新型治疗策略，可通过在线粒体水平有效杀死胶质瘤细胞来提高药物敏感性。在本研究中，我们开发了源自基于线粒体膜的纳米囊泡的人工线粒体，使阿霉素（Dox）能够精确靶向线粒体，通过放大多种细胞死亡途径选择性根除癌细胞。研究发现，包裹阿霉素的基于线粒体的纳米囊泡（DOX-MitoNVs）具有非凡的穿透血脑屏障（BBB）的能力，能够特异性靶向胶质瘤。通过靶向线粒体而非定位于细胞核，DOX-MitoNVs不仅通过细胞内钙超载放大了阿霉素介导的凋亡效应，还通过产生活性氧（ROS）增强了铁死亡。此外，DOX-MitoNVs显示出显著的调节肿瘤免疫微环境的能力，从而诱导明显的免疫原性细胞死亡（ICD）效应。总之，它提出了一种利用DOX-MitoNVs在胶质瘤中进行精确线粒体靶向的新型治疗策略，提高药物敏感性，诱导多种细胞死亡途径，并调节肿瘤免疫微环境以促进免疫原性细胞死亡。意义声明：胶质瘤中的线粒体靶向是一种有前景的治疗策略，可通过利用胶质瘤细胞的线粒体脆弱性来提高药物敏感性。我们设计了基于线粒体膜的纳米囊泡作为人工线粒体，用于阿霉素的精确线粒体靶向。这种方法有助于选择性根除癌细胞，并在免疫原性化疗的同时放大多种细胞死亡途径。值得注意的是，DOX-MitoNVs能有效穿过血脑屏障并特异性靶向胶质瘤。通过聚焦线粒体，阿霉素通过产生活性氧诱导凋亡并增强铁死亡。此外，DOX-MitoNVs可以改变肿瘤免疫微环境，促进免疫原性细胞死亡。总体而言，DOX-MitoNVs为增强胶质瘤治疗提供了一个有前景的平台。
