Nanomaterial Interventions in Pathological Biomolecular Phase Transitions of Neurodegeneration and Cancer

Liquid-liquid phase separation (LLPS) is a physical process that drives the formation of biomolecular condensates, which coordinate cellular biochemical reactions in space and time. Nevertheless, these metastable condensates are susceptible to various disturbances, which trigger the occurrence of abnormal phase transitions. In neurodegeneration, this process promotes the development of misfolded proteins into toxic fibrils. In cancer, LLPS affects multiple stages of its occurrence and progression, including oncogenic signaling, gene expression, angiogenesis, metabolic reprogramming, and invasive growth. The disordered regions of proteins play an important role in these abnormal phase transitions. However, in this area, traditional lock-and-key pharmacology faces major challenges. Notably, due to the large specific surface area, multivalence, and tunability, nanotechnology shows substantial potential for intervention at multiple stages of pathological phase separation. These targets encompass monomers, liquid condensates, oligomers, and fibrils. In addition to traditional strategies, emerging frontiers include nanomaterial-induced synthetic condensates for component sequestration and targeted disruption of oncogenic transcriptional hubs. Furthermore, computational modeling is beginning to transform LLPS research from mechanism discovery toward material rational engineering. This review provides a strategic framework for utilizing nanotechnology as a precision intervention to modulate LLPS, offering a clear path for the intervention of pathological phase separation in diverse diseases.