An agent-guided peptide hydrogel bio-stabilizer clamps pericellular viscoelastic drift.

Living tissues continually remodel the extracellular matrix, causing pericellular mechanics to drift over time. Chronic glycation amplifies this drift, destabilizing mechanoregulatory cues and compromising regenerative outcomes. Here we introduce Micro-Mechanical Homeostasis Reset, a material-based strategy that targets cell-to-pericellular viscoelastic homeostasis rather than static bulk stiffness. Using an agent-guided, rule-based enumeration-and-scoring workflow, we design ViscoClamp, an extracellular matrix-interpenetrating peptide hydrogel with affinity for calcium ions and advanced glycation end products. We show that ViscoClamp buffers chronic glycation loading and constrains glycation-driven viscoelastic drift, while remaining permissive to mesenchymal stem cell-mediated matrix remodeling and mineralization. We quantify stabilization using a dispersion-transfer ratio that measures how variable glycation inputs are compressed into stable micromechanical outputs. We demonstrate that in glycation-rich hyperglycemic craniofacial defects, ViscoClamp stabilizes cell-scale micromechanics, restores osteogenic activation, and improves bone repair and mineralization in rats, rabbits, beagle dogs, and rhesus macaques.