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 userspecified combinations of environmental inputs, nor to independently control the release of multiple species from a homogenous material. In this work, we introduce a modular semisynthetic scheme to govern the release of site-specifically modified proteins from hydrogels following Boolean logic. A sortase-mediated transpeptidation reaction was 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, we exhaustively demonstrate YES/OR/AND control of protein release 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. We expect these methodologies to enable new opportunities in tissue engineering and therapeutic delivery.
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