Phytochemicals as Modulators of Biomolecular Condensates and Liquid–Liquid Phase Separation in Neurodegenerative Diseases: Emerging Mechanisms and Therapeutic Perspectives

Neurodegenerative diseases are increasingly recognized as disorders of cellular proteostasis characterized by progressive protein imbalance, defective stress adaptation, and neuronal dysfunction. Recent discoveries have established biomolecular condensates generated through liquid–liquid phase separation (LLPS) as essential regulators of neuronal organization, coordinating RNA metabolism, protein quality control, stress responses, and intracellular signaling. Alterations in condensate composition, material properties, and turnover are now considered important contributors to the conversion of physiological protein assemblies into persistent pathological structures, thereby influencing the progression of Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, frontotemporal dementia, and related disorders. Natural compounds, including polyphenols, flavonoids, and other phytochemicals, have gained increasing attention due to their broad neuroprotective activities; however, their potential ability to influence condensate biology remains incompletely characterized. This review provides a comprehensive and critical analysis of current evidence connecting natural compounds with biomolecular condensate homeostasis, including direct effects on phase separation as well as indirect regulation through stress granule remodeling, molecular chaperone activity, autophagy, mitochondrial function, oxidative balance, neuroinflammatory pathways, and proteostasis networks. Particular emphasis is placed on the molecular mechanisms through which these bioactive molecules may affect aggregation-associated pathways involving amyloid-β, tau, α-synuclein, TDP-43, and FUS. Finally, current experimental limitations, translational challenges, and future perspectives are discussed, highlighting biomolecular condensates as emerging therapeutic targets and natural compounds as potential multimodal modulators capable of preserving physiological phase behavior while limiting pathological protein maturation. This emerging framework may provide new opportunities for the development of disease-modifying strategies in neurodegenerative disorders.