When designing multi-cellular engineered living systems (M-CELS) composed of multiple cell types, protease activity due to heterotypic interactions must be controlled to prevent M-CELS failure. As we develop multi-cellular engineered living systems (M-CELS), or biological machine (“biobots), with the capabilities to dynamically sense and respond to environmental stimuli, we need to be mindful of the changes in protease profiles that we introduce when bringing multiple cell types together and how this protease activity will lead to remodeling of the extracellular environment.