Logic‐Based Delivery of Site‐Specifically Modified Proteins from Environmentally Responsive Hydrogel Biomaterials

Abstract The controlled presentation of proteins from and within materials remains of significant interest for many bioengineering applications. Though “smart” platforms offer control over protein release in response to a single external cue, no strategy has been developed to trigger delivery in response to user‐specified combinations of environmental inputs, nor to independently control the release of multiple species from a homogenous material. Here, a modular semisynthetic scheme is introduced to govern the release of site‐specifically modified proteins from hydrogels following Boolean logic. A sortase‐mediated transpeptidation reaction is used to generate recombinant proteins C‐terminally tethered to gels through environmentally sensitive degradable linkers. By varying the connectivity of multiple stimuli‐labile moieties within these customizable linkers, YES/OR/AND control of protein release is exhaustively demonstrated in response to one and two‐input combinations involving enzyme, reductant, and light. Tethering of multiple proteins each through a different stimuli‐sensitive linker permits their independent and sequential release from a common material. It is expected that these methodologies will enable new opportunities in tissue engineering and therapeutic delivery.