Sustained Release of Proteins Using Region‐Specific Tunable Degradability in Hydrogels through 3D Photopatterning and Complimentary Labile Bond Chemistry

Abstract Light‐triggered chemical reactions have demonstrated great potential for advanced cell guidance, on‐demand release of therapeutics, and complex patterning in four dimensions. Current strategies rely on the cleavage of a light sensitive bond, while several protein and therapeutic release systems are designed using a hydrolytically labile bond. To bridge the gap between externally controlled light regulated transformations and intrinsically controlled hydrolytically labile bonds, a new family of light‐triggered photocages that upon conjugation to target proteins form more or less hydrolytically (un)stable imine, hydrazone, and oxime bonds is reported. The three photocages follow a dose‐dependent relationship using ultraviolet and near‐infrared radiation and the one‐ and two‐photon uncaging can be controlled in discrete volumes down to at least 10 µm precision. Upon photoirradiation, the exposed latent amino‐, hydrazino‐, and hydroxylamino‐moieties readily react with a variety of proteins, and complimentary sustained release can be achieved. The relative release rate of imine‐, hydrazone‐, and oxime‐bound proteins enable control over cell fate on hydrogels using two neuroblastoma cell lines. These results are anticipated to open new avenues for advanced materials where region‐specifical degradability is central, such as for complex protein photopatterns, cell‐guided hydrogels, and for programmable materials using photomediated dynamic covalent chemistry and photoclick chemistry.