Manipulating the Mitochondrial Unfolded Protein Response for Broad-Spectrum Genotoxicity Mitigation and Tumorigenesis...

Mitochondrial dysregulation, represented by both imbalanced mitochondrial dynamics and dysfunction, has been found as a key driver of cell transformation and tumorigenesis due to enhanced apoptotic priming and genotoxic stress. The mitochondrial unfolded protein response (UPR^mt) represents a protective mechanism that maintains mitochondrial function under mitochondrial damage, making it an attractive target for restoring mitochondrial homeostasis and preventing tumorigenesis. Here, we report an ultrasmall glutathione (GSH)-protected gold nanoparticle (GGNP) that exhibits mitochondrial presence. When mitochondria are damaged by various genotoxic insults, GGNP dramatically activates UPR^mt and improves mitochondrial function without altering mitochondrial dynamics. As a result, GGNP significantly attenuates DNA damage and apoptosis, leading to the prevention of malignant transformation in vitro. More importantly, in a spontaneous lung cancer model, GGNP significantly delays tumorigenesis with reduced DNA damage and cell death within lung tissue without causing systemic toxicity. These findings not only reveal the role of UPR^mt in tumorigenesis but also identify GGNP as a biocompatible nanomaterial that effectively modulates UPR^mt to alleviate mitochondrial stress responses and thus acts as a broad-spectrum genotoxicity mitigator to offer a promising strategy for cancer prevention.