Chirality engineering-regulated liquid-liquid phase separation of stress granules and its role in chemo-sensitization and side effect mitigation

Abstract

In recent years, the chiral biological effects of nanomedicines have garnered significant interest. Research has focused on understanding how material chirality affects cellular transcription and metabolism. Stress granules, which are membraneless organelles formed through liquid-liquid phase separation of G3BP1 proteins and related compartments, have been extensively studied and are closely associated with cellular damage repair and metabolism. The role and mechanism of chiral nanomaterials in modulating stress granules remain unclear. This study aimed to investigate the expression and structural characteristics of stress granules under the influence of chiral nanomaterials, both individually and in combination with chemotherapy. A library of chiral ligand-modified materials was constructed, and techniques such as immunofluorescence, live-cell imaging, fluorescence recovery after photobleaching assays, and proximity labeling combined with proteomics analysis were employed. These methods helped identify the protein corona adsorbed on the surface of the nanomaterials and explore their relationship with nanomaterial chirality. The findings suggest that the assembly of stress granules is influenced by chirality and can be regulated by chiral nanomaterials. Additionally, chemotherapy sensitivity in cancer cells was enhanced, and normal cells were protected by leveraging the chiral-dependent modulation of material assembly in stress granules. This study offers insights into the regulation of membraneless cellular structures based on chiral biological effects.

Keywords: Chemotherapy; Chirality; Liquid–liquid phase separation; Nanomedicine; Stress granules.