Mast cell extracellular granules are bioactive condensates assembled by heparin and polyamine

Biomolecular condensates are membraneless bodies that organize biochemical reactions typically within cells. However, the roles of condensates in extracellular space-where conditions differ substantially from intracellular space-remain poorly understood. Here we report that mast cell extracellular granules (MCEGs), a stable membraneless entity, are condensates assembled through electrostatic interactions between glycosaminoglycans and polyamines. Disrupting polyamine synthesis or trafficking blocks MCEG formation and compromises the storage of proteases and cytokines. Granules reconstituted with heparin and spermine are sufficient to enrich mediators such as carboxypeptidase A3 (CPA3) and tumor necrosis factor (TNF), maintaining an elevated pH and higher concentrations of calcium and zinc compared to the extracellular milieu. This unique environment enhances CPA3 enzymatic activity. Furthermore, the granules increase TNF binding and its bioactivity toward endothelial cells. Together, we reveal MCEGs as functionally active biomolecular condensates with distinct biochemical and immunological properties; MCEGs are formed through sugar-metabolite interactions, expanding the mechanisms of condensate assembly beyond classical protein-protein and protein-RNA interactions.