Molecular Basis of Graphene-Induced Oxidative Stress and Mitochondrial Signaling in Target Cells: Consequences for Therapeutic Window and Design of Redox-Responsive Payloads

Graphene nanomaterials (GNMs) have emerged as a unique class of bioactive interfaces capable of directly modulating cellular redox homeostasis and mitochondrial function through their distinctive physicochemical and electronic properties. Unlike conventional nanocarriers, GNMs participate in electron transfer reactions, catalyze reactive oxygen species (ROS) generation and interact dynamically with biomolecular systems, thereby influencing signaling pathways that govern metabolism, inflammation and cell fate. At the molecular level, structural attributes such as oxidation state, defect density, lateral size and surface functionalization determine the balance between adaptive redox signaling and pathological oxidative stress. These interactions converge on mitochondria, where disruption of electron transport, membrane potential and antioxidant defenses can trigger diverse cell death modalities including apoptosis, ferroptosis, necroptosis and pyroptosis. Importantly, disease-specific vulnerabilities such as elevated basal ROS in cancer, mitochondrial fragility in neurodegeneration and metabolic dysregulation in chronic disorders can be strategically exploited to achieve therapeutic selectivity. Advances in redox-responsive engineering organelle targeting and nanozyme design are enabling graphene-based systems to function as programmable platforms for controlled drug release and bioenergetic modulation. Coupled with systems biology approaches and safety-by-design strategies, these developments are redefining the therapeutic window of graphene from a toxicity concern to a tunable biomedical opportunity. This review integrates mechanistic insights with translational design principles, outlining how graphene’s redox activity can be harnessed to develop precision nanomedicines that operate at the interface of materials science, mitochondrial biology and clinical therapeutics. • Graphene acts as a bioelectronic interface rewiring cellular redox flow pathways. • Physicochemical defects govern ROS catalysis and mitochondrial targeting specificity. • Mitochondrial interactions convert oxidative cues into apoptosis or ferroptosis. • Disease redox vulnerabilities enable selective therapeutic amplification by graphene. • Redox-responsive functionalization enables on-demand drug release in diseased tissue. • Safety-by-design strategies tune electron transfer to widen the therapeutic window.