Metal Ion Chelation by Nanoparticles in Alzheimer's Disease Targets Ferroptosis and Cuproptosis as Convergent Therapeutic Pathways

Despite decades of research focused on proteopathy in Alzheimer’s disease (AD), amyloid- and tau-based therapies have failed to effectively modify the course of the disease. This failure highlights the need for a mechanistic redefinition, in which the simultaneous disruption of iron and copper homeostasis, through the induction of ferroptosis and cuproptosis, is introduced as an upstream and complementary driver of proteopathic damage. The mechanistic integration of these two distinct yet interconnected and metal-dependent cell death pathways into the pathophysiology of AD remains poorly defined. In this article, we present an integrated model that introduces metal chelation by engineered nanoparticles not only as an antioxidant strategy, but also as a targeted intervention that addresses the convergence points of ferroptosis and cuproptosis. We delineate the molecular mechanisms of ferroptosis and cuproptosis and examine convergent biochemical vulnerabilities, particularly disruption of glutathione-dependent redox control, mitochondrial metabolism, and metal handling. Available evidence suggests that these shared vulnerabilities may increase cellular susceptibility to both forms of metal-dependent stress, while direct mechanistic coupling between ferroptosis and cuproptosis in AD remains incompletely established. Against this background, engineered nanoparticles are considered potential carriers for selectively modulating pathological iron and copper pools while preserving essential metal-dependent functions. This paradigm supports the investigation of metal-homeostasis-restoring nanotherapies as a potential disease-modifying strategy, while emphasizing the need for mechanistic validation, pathological-metal selectivity, and rigorous translational assessment.