Nanoplastic exposure and protein aggregation in neurodegenerative and neurodevelopmental disease: a systematic review

Nanoplastics and microplastics (NMPs) are now detectable across environmental compartments and, increasingly, in human tissue including blood, placenta, and post-mortem brain samples. A growing body of mechanistic, biophysical, and toxicological literature links NMP exposure to protein aggregation processes — including α-synuclein, amyloid-β, tau, TDP-43, huntingtin, and prion protein — that are central to the pathophysiology of neurodegenerative diseases (Parkinson's disease, Alzheimer's disease, Huntington's disease, ALS/motor neuron disease, frontotemporal dementia, prion disease) and, separately, to neurodevelopmental outcomes (autism spectrum disorder, ADHD, intellectual disability, and related conditions). This evidence base has expanded rapidly since approximately 2018, spanning cell-free biophysical aggregation assays, cell-based in vitro studies, in vivo animal models (rodent, zebrafish, C. elegans, Drosophila, and other non-human models), and a small but growing number of human tissue studies. A separate, smaller body of molecular-dynamics/computational evidence — simulating the interaction of neurodegeneration-associated proteins with plastic polymer surfaces — provides complementary mechanistic insight (adsorption thermodynamics, protein conformational change) not resolvable by experimental methods alone; this review treats this computational evidence as a distinct, clearly labeled stream, appraised on its own terms and never pooled with experimental effect-direction findings. Despite this volume of publication, the field lacks a systematic synthesis that evaluates the evidence across the full range of neurodegenerative and neurodevelopmental outcomes and protein targets, rather than focusing on a single disease or single protein. It also lacks a systematic appraisal of the methodological reliability of the underlying studies — specifically, the extent to which laboratory-used particles (predominantly commercial, monodisperse polystyrene spheres) are physically and chemically characterized in a way that supports comparison across studies (polymer identity verification, particle size and morphology, surface chemistry, and colloidal behavior in the exposure medium); whether endotoxin or other contamination in commercial particle preparations has been controlled for and could confound reported neuroinflammatory effects; whether exposure doses used in experimental models are comparable to estimated human exposure levels; and whether dosimetry — including particle number and surface-area concentration, not mass concentration alone — is reported in a standardized, comparable way across studies. Purpose. This systematic review aims to (1) synthesize the existing experimental evidence on the relationship between nano-/microplastic exposure and protein aggregation and/or neurodegenerative/neurodevelopmental disease-relevant outcomes across cell-free, in vitro, in vivo, and human study designs, alongside a separately reported computational/molecular-dynamics evidence stream; (2) map this evidence across polymer types, particle characteristics, exposure paradigms, and outcome measures; and (3) systematically appraise the methodological quality and translational validity of the included studies, using design-matched appraisal tools (including a structured particle-characterization checklist and, for the computational stream, a dedicated simulation-quality checklist), with particular attention to particle characterization completeness, contamination control (including endotoxin), dose-to-human-exposure relevance, and dosimetry reporting standards. Expected outcomes. The review will produce a PRISMA 2020-compliant narrative synthesis describing the mechanistic, biophysical, model-based, and human evidence linking NMP exposure to protein aggregation and neurodegenerative/neurodevelopmental outcomes; a structured risk-of-bias and particle-characterization quality appraisal of the included literature; a separately reported synthesis of the computational/molecular-dynamics evidence stream; and an explicit account of translational gaps between laboratory models and real-world environmental exposure. Where a sufficiently homogeneous subset of studies is identified during data extraction, a limited exploratory meta-analysis of that subset will additionally be conducted. This review is planned as a living review, with the search strategy re-executed approximately annually to keep the evidence base current. The review is intended to serve as a methodologically-focused reference point for this emerging field and to inform future study design (e.g., recommendations on particle characterization, dosimetry reporting, and contamination controls) rather than to add another general narrative on NMP neurotoxicity to the existing literature.