Intranasal nanoparticle therapy for arsenic-induced neurotoxicity: Restoring IGF-1 signaling and advancing translational neuroprotection

Insulin-like growth factor-1 (IGF-1) is a critical neurotrophic hormone involved in central nervous system (CNS) development and neuroprotection, primarily through its regulation of the PI3K/AKT and MAPK/ERK signaling pathways. Chronic exposure to arsenic, a prevalent environmental neurotoxin, has been increasingly associated with IGF-1 signaling disruption, resulting in oxidative stress, neuronal apoptosis, cognitive dysfunction, and progressive neurodegeneration. This review provides a comprehensive analysis of the mechanistic interplay between arsenic-induced neurotoxicity and IGF-1 pathway impairment, emphasizing the molecular and functional consequences on brain health. To address these challenges, we explore emerging nanotechnological strategies, specifically, nanoparticle (NP)-based drug delivery systems, as promising therapeutic tools. Particular attention is given to intranasal delivery platforms such as liposomes, solid lipid NPs, nanoemulsions, and cubosomes that encapsulate both synthetic and natural neuroprotective agents. Notably, this review presents, for the first time in this context, a comparative evaluation of these NP systems, highlighting their respective advantages, limitations, and brain-targeting capabilities. In addition to synthesizing preclinical evidence, we critically assess translational barriers to clinical implementation, including regulatory hurdles, scalability, and long-term safety considerations. By integrating insights from neurotoxicology, nanomedicine, and translational neuroscience, this review offers a novel perspective on counteracting arsenic-induced cognitive decline and proposes a potential paradigm shift in the treatment of environmentally driven neurodegenerative disorders.