Controlling Linear and Non‐Linear Mechanics in Multicomponent Hydrogels Through Programmable Supramolecular and Covalent Interactions

ABSTRACT In our native extracellular matrix (ECM), hierarchical interactions—supramolecular and covalent—between multiple components give rise to complex mechanical properties. Reproducing such emergent properties in synthetic hydrogels remains challenging, particularly the non‐linear mechanics. Here, we engineer fully synthetic, multi‐component hydrogels that possess tunable (non)‐linear mechanics by programmable supramolecular and covalent interactions. To achieve this, the stress‐stiffening polyisocyanide (PIC) polymer is combined with the supramolecular ureido‐pyrimidinone (UPy)‐based polymer through (A) supramolecular mixing and (B) covalent mixing (UPy‐functionalized PIC). By changing the type of interaction, (1) the linear mechanics could be tuned from G′ ~700 to 1600 Pa, and (2) the non‐linear mechanics was programmed with tunable sensitivity (critical stresses between ~20 and 65 Pa) and responsiveness (stiffening indices ranging from ~0.6 to 1.1). These programmable mechanical properties were biologically relevant: cells adhered and elongated in the multi‐component hydrogels, whereas they remained round in softer single‐component controls. Interestingly, cells preferentially spread in supramolecularly mixed hydrogels compared to covalently coupled hydrogels, likely due to increased network remodelability and larger pore sizes. Together, these results establish a modular strategy to engineer ECM‐inspired hydrogels in which programmable inter‐network interactions generate emergent linear and non‐linear mechanics that direct cellular behavior.