Photoresponsive Granular Hydrogels Enable Spatiotemporal Control of Matrix Mechanics and MSC Behavior.

Granular hydrogels offer a powerful platform for engineering porous, cell-instructive scaffolds with tunable mechanical, structural, and biochemical properties, yet introducing spatial and functional heterogeneity typically requires multiple microgel populations or complex fabrication strategies. Here, we present a programmable, photoresponsive granular hydrogel platform that enables post-assembly spatiotemporal control of scaffold mechanics and cell microenvironments from a single microgel formulation. Poly(ethylene glycol) microgels containing photolabile allyl sulfide moieties were synthesized via strain-promoted azide-alkyne cycloaddition and assembled into granular scaffolds capable of light-mediated remodeling through radical addition-fragmentation chain transfer. This chemistry afforded dynamic, on-demand, and spatially defined tuning of mechanical properties (G' = 0.7-3.7 kPa) while maintaining scaffold porosity (∼20%). High-resolution photopatterning across multiple length (6 µm-1 mm) and timescales enabled precise modulation of local microenvironments. Human mesenchymal stem/stromal cells embedded in these scaffolds responded to spatiotemporal modulation of matrix mechanics as observed by changes in morphology, yes-associated protein 1 (YAP) nuclear localization, and secretory profiles. Together, these results establish a versatile and broadly applicable strategy for programming mechanical heterogeneity and regulating cell behavior in granular hydrogels through photolabile moieties.