Redox-modulating metallic nanoparticles: mechanistic insights into pharmacological activity and cellular therapeutics

Redox imbalance refers to abnormal production of reactive oxygen species (ROS) and reactive nitrogen species (RNS), which causes cellular dysfunction and damage, playing a critical role in the onset and progression of many diseases including cancer, cardiovascular disorders, and neurodegenerative conditions such as Alzheimer's and Parkinson's disease. While many previous reviews have covered individual systems of nanoparticles (NP) or single disease applications separately, there is a missing link that has not been adequately summarized regarding the ability of the same metallic core to act as an antioxidant or pro-oxidant, depending on dose, local pH, and surface chemistry. This review addresses that gap by tracing redox modulation from physicochemical origins through intracellular signaling to clinical translation across oncology, infectious diseases, and neurodegeneration. Metallic NPs such as gold, silver, copper, zinc oxide, iron oxide, and cerium-based systems have emerged as transformative tools in modern pharmacology due to their unique physicochemical properties including high surface-to-volume ratio. NPs act as redox modulators by scavenging excess oxidants through enzyme-mimetic activities like superoxide dismutase and catalase or selectively causing cytotoxicity in pathological environments. NPs interact with intracellular organelles and affect signaling pathways like Nrf2, NF-κB, and MAPK. Transition metal nanoparticles catalyze Fenton reactions that generate toxic hydroxyl radicals in the acidic and glutathione-rich tumor microenvironment, leading to programmed cell death through apoptosis, ferroptosis, and cuproptosis. Green synthesis of NPs using plant extracts and microorganisms reduces toxic byproducts and improves biocompatibility and stability. Redox-modulating metallic NPs have shown promise in preclinical models for tumoricidal, anti-inflammatory, and antibacterial uses. Although agents such as Ferumoxytol and Hensify have reached clinical application, challenges regarding long-term toxicity, immunogenicity, and systemic clearance remain. Future directions in this field emphasize the development of stimuli-responsive nanoplatforms for scientifically controlled and reproducible cargo release and the integration of computational tools to predict biological interactions. These advances are expected to provide deeper mechanistic insights into pharmacological activity at the nano-bio interface.