One defining feature of complex organisms is the ability to maintain protein homeostasis beyond cellular boundaries. We review how extracellular proteostasis is organized as a hierarchical network spanning pericellular, tissue, and systemic tiers. At each tier, secreted chaperones, proteases, vesicles, receptors, immune sentinels, and clearance organs cooperate to recognize, buffer, and eliminate misfolded proteins. Feedback through immune signaling, stress-induced protein secretion, and glymphatic and lymphatic transport adjusts capacity to proteotoxic load. We illustrate how failures in this stratified defense underlie neurodegenerative disorders and systemic amyloidoses, and we highlight strategies that stabilize extracellular proteins, augment clearance pathways, or enhance fluid transport. Viewing extracellular proteostasis as an integrated systems-level network reveals opportunities for combinatorial and preventive therapies.
Gomes et al. (2026) studied this question.