Nanomaterial modulation of lysosomal homeostasis in neurodegenerative proteinopathies: from pathological-protein degradation to re-release and seeding.

Misfolded and aggregated proteins are central to neurodegenerative proteinopathies, yet a reduction in intracellular protein burden does not necessarily indicate productive clearance, because incompletely processed cargo may be re-released and retain seeding competence. This review examines how nanomaterials targeting lysosomal homeostasis may promote complete degradation of pathological proteins while limiting the re-release of incompletely processed species and their residual seeding activity. PubMed records published from July 2021 to July 2026 were prioritised, with earlier foundational studies included selectively, and evidence was classified as direct disease-model evidence, mechanistic support, or platform extrapolation. Across Aβ, tau, α-synuclein, polyglutamine-expanded proteins, and SOD1-related pathology, effective clearance depends on protein conformation, cell type, lysosomal acidification and hydrolase activity, autophagic transport, lipid processing, membrane integrity, and cellular bioenergetics. Current evidence is strongest for restoration of lysosomal acidity, hydrolase function, and autophagic processing; support for durable lipid and membrane correction is less complete, and direct evidence for reduced re-release and seed inactivation remains scarce. No reviewed study simultaneously demonstrated lysosomal restoration, complete degradation of a defined pathological substrate, reduced extracellular release, and direct seed inactivation. Future evaluation should therefore integrate brain, cell-specific and organelle delivery, substrate turnover, extracellular cargo, direct seeding assays, and repeated-dose lysosomal safety.