From ROS to Cuproptosis: The molecular evolution of copper nanotherapeutics

The renewed interest in copper-based materials for biomedical applications has been catalyzed by advances in nanotechnology, shifting the paradigm from empirical antimicrobial therapies toward multifunctional nanoplatforms capable of targeted intervention and theranostic integration. This work provides a systematic assessment of the developmental trajectory of copper-containing nanostructures-ranging from single-component Cu, CuO, and Cu₂O particles to shape-anisotropic architectures, polymer composites, and ultimately bimetallic combinations, with particular emphasis on Cu/Se systems. A central thesis advanced here is that the bioactivity of these agents cannot be attributed to a single intrinsic parameter; rather, it emerges from a convoluted interplay of size, morphology, surface potential, oxidation state, shell composition, and, notably, the aggregation behavior in physiological fluids-the latter being frequently obscured by protein corona artifacts. Moving beyond conventional reactive oxygen species (ROS)-driven oxidative injury and mitochondrial apoptotic cascades, recent molecular toxicology has identified two non-apoptotic, copper-relevant cell death modalities: cuproptosis, characterized by aggregation of lipoylated mitochondrial proteins via the ferredoxin 1 (FDX1), and ferroptosis, involving glutathione peroxidase 4 (GPX4) inhibition and intracellular glutathione exhaustion. These pathways, together with the phenomenon of cuproplasia in malignant cells, offer unprecedented opportunities for selective therapeutic intervention. Among all structural classes, bimetallic Cu/Se nanoparticles represent a "reconciliation of redox opposites," wherein the pro-oxidant Fenton-like activity of copper is counterbalanced by selenium's antioxidant, photothermal (conversion efficiency exceeding 80%), and regulatory functionalities, leading to substantially improved therapeutic indices and diminished off-target effects. Anisotropic configurations-including nanoflowers and nanorods-further enable multimodal diagnostic imaging and combined therapy, yet their clinical translation is constrained by difficulties in morphological reproducibility and in vivo clearance mechanisms. While clinical adoption remains largely confined to topical indications (e.g., CuO-embedded wound dressings that have demonstrated significant reductions in surgical site infections in randomized trials), the emerging mechanistic framework centered on cuproptosis and hypoxia-inducible factor 1α (HIF-1α) modulation positions copper-based nanoplatforms as strong contenders for future theranostic applications. The review concludes that the field must prioritize a "clearance-by-design" philosophy, implement standardized green synthesis protocols, and conduct comprehensive long-term biodistribution and toxicity studies in vivo to close the existing gap between robust preclinical evidence and tangible clinical impact.