Significance Over the past two decades, natural protein-based hydrogel biomaterials have catapulted cell biology into the third dimension, becoming the modern workhorses of 3D cell and organoid culture. Although these systems mimic many important aspects of native tissue while permitting matrix remodeling and biological integration, spatiotemporal control over cell fate within these materials has not been demonstrated. Here, we introduce a generalizable strategy to covalently decorate cell-laden natural hydrogels with bioactive proteins including growth factors and then use these methods to anisotropically govern cell fates in ways currently unobtainable in synthetic biomaterials. Enabling 4D biochemical tunability within natural protein-based gels, these approaches are likely to find great utility in probing and directing biological functions and in engineering heterogenous functional tissues.