Mg ²⁺ -Dependent Remodeling of Biomolecular Condensates’ Microenvironments for Tunable Molecular Uptake and Altered Biochemical Dynamics

Biomolecular condensates have emerged as a transformative paradigm in biomedical and materials sciences due to their unique capacity for molecular sequestration and dynamic adaptability. Precise modulation of their microenvironmental properties enables versatile applications including protocell engineering, targeted therapeutics, and smart bioreactor systems. Here, we demonstrate that multivalent ions, exemplified by magnesium ions (Mg2+), exert concentration-dependent regulation of condensate physicochemical properties and biological functions. Using a model system composed of cationic arginine decamer (R10) and anionic polyglutamate (PolyE), we systematically show that Mg2+ concentration gradients influence the size distribution, surface charge, viscosity, and internal polarity. Critically, we establish links between ion-induced microenvironmental changes and functional outcomes: (i) dsDNA structural stability and ssDNA hybridization kinetics are altered in an ion-dependent manner; (ii) guest molecule enrichment capacity shows selective tuning; and (iii) alkaline phosphatase (ALP) catalytic efficiency exhibits nonlinear dose–response relationships. These findings offer mechanistic insights into cellular ion homeostasis and provide design principles for ion-responsive synthetic condensates with programmable functionality. Our work bridges fundamental biophysical principles with translational applications in smart biomaterials and precision medicine.