Non‐Stoichiometric Amorphous Calcium Carbonate Forms in Macromolecular Condensates via Interphase Diffusion

Abstract Transient amorphous phases are known as functional precursors in the formation of crystalline materials, both in vivo and in vitro. A common route to regulate amorphous calcium carbonate (ACC) crystallization is via direct interactions with negatively charged macromolecules. However, a less explored phenomenon that can influence such systems is the electrostatically driven formation of Ca‐macromolecule dense phases. In this study, it is shown how Ca‐macromolecule condensates that form via liquid–liquid phase separation (LLPS) can be used to control the formation of metastable ACC via diffusion‐based mass transport. Contrary to the solid‐like ACC particles that form in the dilute phase via rapid nucleation and growth, the condensate ACC gradually forms via carbonate diffusion into the dense droplets. This yields transient phases with non‐stoichiometric compositions, similar to a solid solution. It is shown that the ability to control the concentration gradients across the phase boundary can be used to finely regulate the composition and stability of these amorphous precursors, offering new routes to control mineralization through transient phases.