Nanoplastics-induced neurotoxicity: neurovascular dysfunction, cognitive impairment, and mechanisms of cell death

Nanoplastics (NPs) are increasingly recognized as environmentally persistent contaminants capable of reaching the central nervous system (CNS), yet the mechanistic basis linking brain exposure to cognitive dysfunction remains incompletely resolved. Emerging evidence indicates that NPs can cross or perturb the blood-brain barrier (BBB), accumulate within neural tissues, and interact with neurons, microglia, astrocytes, neural progenitors, and cerebrovascular cells. These interactions have been associated with oxidative stress, mitochondrial dysfunction, neuroinflammation, synaptic injury, and disruption of hippocampal homeostasis, although the strength and causal nature of evidence for individual mechanisms vary across experimental models. Importantly, regulated cell death (RCD) is emerging as a critical mechanistic bridge between cellular toxicity and neurocognitive outcomes, encompassing apoptosis, pyroptosis, ferroptosis, and cuproptosis. However, evidence for specific cell-death pathways remains largely based on molecular and cellular signatures in experimental models, and oxidative stress, mitochondrial dysfunction, or altered expression of pathway-associated proteins alone should not be considered definitive evidence of pathway activation. Recent studies further implicate microglial extracellular traps, excessive mitochondrial fission, and glymphatic dysfunction as potentially important pathways connecting NP exposure with neuronal injury and cognitive decline. Environmental co-exposures may intensify these effects, highlighting the context-dependent nature of NP neurotoxicity. This review integrates current evidence linking NP exposure to cognitive and behavioral abnormalities, emphasizing the interconnected roles of neurovascular dysfunction, glial-neuronal crosstalk, oxidative-mitochondrial stress, synaptic disruption, RCD, and impaired brain clearance mechanisms.