Over recent decades, the relentless accumulation of plastic waste in terrestrial and aquatic environments has emerged as a critical global concern, giving rise to a new class of pollutants microplastics (MPs) and nanoplastics (NPs) [1]. Despite their minuscule dimensions, NPs pose disproportionate biological risks due to their small size (<200 nm), chemical stability, high surface reactivity, and capacity to interact with living systems at the cellular and molecular levels [2,3]. With global plastic production projected to surpass 1.2 billion tonnes by 2060 and recycling rates remaining alarmingly low, the environmental and biological burdens of micro- and NPs are intensifying at an unprecedented scale [4]. These NPs have permeated every environmental compartment. Recent analytical techniques detected these NPs in indoor and outdoor air, drinking water, beverages, and a variety of food items including seafood, salt, vegetables, and processed foods. Airborne NPs are present in urban atmospheres and indoor environments, indicating inhalation as a significant exposure route [5,6]. In drinking water, NPs have been observed at concentrations ranging from ∼2.4 × 105 particles per liter up to ∼1 × 1011 particles per liter in bottled water [[7], [8], [9]]. Studies on food and beverages have shown that plastic packaging and tea bags can release very high numbers of NPs (∼3.1 × 109 NPs per cup) during routine use, suggesting ingestion as another major exposure pathway [[10], [11], [12]]. Estimated human intake of NPs through combined inhalation and ingestion has been reported in the range of ∼104–106 particles per day, although these numbers are likely underestimates due to analytical limitations for particles below detection thresholds [5,6]. Importantly, current monitoring techniques significantly underestimate NPs due to detection limits below ∼1 μm and lack of standardized analytical protocols, suggesting that real-world exposure is likely much higher than presently reported [5,9,13]. Environmental monitoring studies have reported NPs concentrations reaching approximately 0.04 mg/mL in aquatic systems and 5–55.5 mg kg−1 in soils, indicating substantial environmental loading [14]. These levels are highly relevant for dietary exposure, as NPs undergo trophic transfer and bioaccumulate in food matrices, including aquatic organisms and agricultural products. Consequently, organisms may experience effective internal exposure levels that exceed those measured directly in environmental media. This raises urgent concerns for both ecological balance and human health, particularly about their potential health impacts [3,15,16].

The neurological impacts of NPs represent a particularly concerning area of toxicity. Recent analytical breakthroughs have confirmed that NPs not only enter peripheral tissues (lungs, placenta, kidneys) but also accumulate in the brain. Frontal cortex samples revealed median concentrations of 3.3 mg g−1 to 4.9 mg g−1, with particles predominantly composed of polyethylene (≈75%), followed by polypropylene, polyvinyl chloride and polystyrene. Strikingly, dementia and Alzheimer's patients exhibited ∼5-fold higher levels (∼26 mg g−1), suggesting enhanced NPs deposition under neurodegenerative conditions [17,18]. This discovery has intensified concerns about the potential neurotoxic effects of NPs, especially as both laboratory and epidemiological studies now link MNPs exposure to cognitive dysfunction and increased risk for neurological disorders [[17], [18], [19]]. While early research focused on the systemic and peripheral toxicity of NPs, a growing body of animal and cellular studies reveal that PS-NPs can cross the blood–brain barrier (BBB) via multiple routes, breach neural tissues, and disrupt the homeostasis of neurons and glia. The olfactory bulb has been identified as a plausible entry point, enabling MPs to bypass the BBB and potentially access deeper brain structures. Once inside the brain, these particles can induce oxidative stress, neuroinflammation, and apoptosis, all critical pathological mechanisms underlying neurodegeneration [20]. Experimental studies demonstrate that exposure to PS-NPs (size 40–53 nm) at concentrations of 10–100 mg L−1 leads to behavioral impairments in aquatic vertebrates indicating the neurotoxic potential of nanoscale plastics [21]. Furthermore, rodent experiments revealed that chronic oral exposure to 60 nm sized PS-NPs (12.5 mg kg−1 day−1 for 30 days) significantly impaired learning and memory [22]. An expanding body of preclinical evidence implicates NPs in the disruption of neural development and brain physiology [21]. Recent study has shown that anionic PS-NPs (Size ∼100 nm) can form high-affinity complexes with the amphipathic and non-amyloid component domains of α-synuclein, identifying a potential mechanistic link between NPs exposure (1 nM or 10 to 15 μg mL-1) and PD–related synucleinopathies [23].

Moreover, behavioral abnormalities have been observed across diverse aquatic species, including nematodes, crustaceans, and fish, following NPs exposure. Structural and functional impairments of nerve fibers, along with deficits in locomotor activity and enzymatic functions, have also been documented. High-resolution human postmortem studies further highlight the urgent need to understand the consequences of cerebral plastic accumulation, as dementia cases not only have greater plastic burden but may also be exposed to compounding processes such as barrier breakdown and reduced clearance. Taken together, these findings underscore the neurotoxic potential of NPs and highlight the urgent need for studies to assess their long-term effects on brain health.

The brain is a lipid-rich organ, with nearly 50–60% of its dry weight composed of complex lipids that are essential for membrane architecture, synaptic transmission, and signaling. Even subtle perturbations in brain lipid metabolism can disrupt neuronal communication, mitochondrial function, and neuroinflammatory balance, thereby predisposing to neurodegenerative processes [24]. In the current neurotoxicological paradigm, such lipid metabolic disturbances can act as early molecular events preceding overt pathology, particularly under environmental stressors like NPs exposure. Lipidomics is the comprehensive analysis of lipidomes using high-resolution accurate mass spectrometry (HRAMS) enables offering a sensitive readout of the brain metabolic state. In this context, high-throughput MS-based lipidomics can uncover alterations in lipid metabolites that are critical for neuronal membrane integrity, neurotransmitter release, and oxidative stress regulation. Moreover, cumulative shifts in lipid composition and distribution in response to external stressors like NPs can provide valuable insights into the physiological status, and lipids themselves can act as critical regulators of cellular function and phenotype [[25], [26], [27], [28], [29], [30]].

Despite the brain vulnerability to environmental stressors, NPs-induced perturbations of endogenous brain lipid species remain largely unexplored, representing a major knowledge gap in neurotoxicology. We hypothesized that chronic exposure to polystyrene nanoplastics (PS-NPs) disrupts mitochondrial membrane lipid composition, leading to redox imbalance, impaired bioenergetics, and subsequent dopaminergic neurodegeneration. Accordingly, the primary objectives of this study were to: (i) map PS-NPs–induced alterations in the brain lipidome using untargeted high-resolution lipidomics; (ii) investigate mitochondrial functional consequences; (iii) evaluate downstream neurochemical and behavioral outcomes relevant to Parkinson's disease pathology; and (iv) determine whether antioxidant intervention with N-acetylcysteine (NAC) can rescue these metabolic and functional defects.

To address these objectives, Drosophila melanogaster was employed as an experimental model due to its high genetic and functional conservation with the human nervous system, sharing ∼75% of human disease-related genes, making it a powerful platform for neurotoxicity studies. To model environmental toxicity, Drosophila flies were chronically exposed to PS-NPs at two concentrations (0.01 and 0.05 mg/mL). Using an integrative strategy, we combined untargeted lipidomics with mitochondrial functional assays, neurotransmitter profiling, behavioral analyses, and stable isotope tracing to systematically evaluate NPs-induced metabolic reprogramming. This experimental design enabled mechanistic interrogation of how NPs disrupt mitochondrial redox homeostasis, lipid metabolism, and dopaminergic function, and further allowed assessment of antioxidant-mediated rescue using NAC. To our knowledge, this is the first study to comprehensively characterize NPs-driven brain lipid remodeling using an integrated lipidomics and mitochondrial redox profiling approach.