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

Abstract

Mitochondrial targeting in gliomas represents a novel therapeutic strategy with significant potential to enhance drug sensitivity by effectively leveraging the inherent vulnerabilities of glioma cells at the mitochondrial level. In this study, we developed a sophisticated nano-delivery system by engineering artificial mitochondria from mitochondrial membrane-based nanovesicles, enabling precise targeting of doxorubicin (Dox) to selectively eradicate cancer cells while amplifying multiple cell death pathways. It was found that Dox-encapsulating mitochondria-based nanovesicles (DOX-MitoNVs) have exhibited an extraordinary ability to penetrate the blood-brain barrier (BBB), specifically targeting gliomas. By targeting mitochondria instead of infiltrating the nucleus, DOX-MitoNVs not only amplified Dox mediated apoptosis effects through the overload 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 artificial mitochondria from mitochondrial membrane-based nanovesicles as a novel nano-delivery system for precise targeting of Doxorubicin (Dox). This approach facilitates selective cancer cell eradication and amplifies multiple cell death pathways alongside immunogenic chemotherapy. Notably, Dox-encapsulating mitochondria-based nanovesicles (DOX-MitoNVs) effectively cross the blood-brain barrier (BBB) and specifically target gliomas. By focusing on mitochondria, Dox induces apoptosis and intensifies ferroptosis through reactive oxygen species (ROS) generation. Additionally, DOX-MitoNVs can transform the tumor immune microenvironment, promoting immunogenic cell death (ICD). Overall, DOX-MitoNVs offer a compelling platform for enhanced glioma therapy.