Mitochondrial transfer of drug-loaded artificial mitochondria for enhanced anti-Glioma therapy through synergistic apoptosis/ferroptosis/immunogenic cell death

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 Ca²⁺ 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.