Photo‐Responsive Peptide Hydrogels with Tunable Stiffness via Water Switching for Cell Fate Regulation

Abstract Photo‐responsive peptide hydrogels are ideal for mimicking the extracellular matrix (ECM) with dynamic stiffness to regulate cellular behaviors. However, achieving reversible stiffness modulation without greatly altering gel composition or structure, which may interfere with stiffness‐dependent cell responses, remains challenging. Here, a bio‐inspired peptide hydrogel is reported, whose modulus can be reversibly regulated via a hydration‐mediated “water switch” upon light stimuli. Spiropyran (SP) units are integrated into DFYD‐based peptides to construct a co‐assembled hydrogel, with a low critical gelation concentration of 0.2 wt.%. In the zwitterionic, ring‐opened merocyanine (MC) state, the gel retained more water and remained soft. Upon visible light irradiation, MC/SP isomerization reduced polarity, expelled water from the gel, and increased stiffness. The gels exhibited excellent biocompatibility in both states and highlighted enhanced cell proliferation and differentiation through light‐controlled modulation of stiffness. This work provides a new strategy for constructing smart hydrogels for regenerative therapy applications.