Chronic Lead Exposure and Tauopathies: Molecular Mechanisms of Neurotoxicity and Emerging Nanotherapeutic Strategies.

Chronic exposure to lead (Pb) remains a critical global public health challenge, extending beyond its established neurotoxic effects to its emerging role in the pathogenesis of neurodegenerative disorders, particularly tauopathies. Accumulating evidence indicates that prolonged Pb exposure disrupts neuronal homeostasis through multiple interconnected mechanisms, including oxidative stress, mitochondrial dysfunction, neuroinflammation, epigenetic alterations, and dysregulation of tau phosphorylation. These molecular perturbations contribute to synaptic impairment, neuronal loss, and progressive cognitive decline. Current therapeutic strategies primarily rely on metal chelation and antioxidant interventions; however, their clinical efficacy is limited by poor blood-brain barrier penetration, nonselective metal removal, and systemic adverse effects. Recent advances in nanotechnology offer promising alternatives for targeted neuroprotection. Nanocarrier systems, including dendrimers, liposomes, polymeric nanoparticles, and micelles, enable enhanced brain delivery, controlled drug release, and reduced systemic toxicity. This review synthesizes current knowledge on the molecular mechanisms linking Pb exposure to tau-related neurodegeneration and critically evaluates existing therapeutic approaches. Furthermore, it highlights the potential of nano-based delivery systems to overcome the limitations of conventional therapies and outlines future directions for translational research in Pb-associated neurodegenerative disorders.