Phase Separation, Material State, and Condensate Fate in Mammalian Autophagy.

Biomolecular phase separation has emerged as a key organizing principle in macroautophagy (hereafter autophagy). In mammalian cells, phase-separated condensates not only serve as substrates for selective degradation, but also act as dynamic platforms for cargo recognition, signaling integration, and autophagosome assembly. The material state of these condensates is an important determinant of autophagic fate. Condensates exist along a continuum ranging from liquid-like droplets to gel-like and solid assemblies, and their progressive maturation can alter accessibility to autophagic machinery. Scaffold proteins and selective autophagy receptors further organize these assemblies into degradation-competent mesoscale reaction fields that couple cargo recognition with phagophore formation. Dysregulation of this phase separation-autophagy axis is increasingly implicated in neurodegeneration, cancer, aging, and stress-associated degenerative disease. Here, we propose a multiscale framework in which molecular accessibility, mesoscale organization, and condensate state transitions collectively shape autophagic outcome, providing a conceptual basis for predictive models and therapeutic strategies aimed at restoring condensate degradability.