Mammalian synthetic biology offers promising tools to create “smart” cellular therapies to tackle complex diseases like cancer. However, current tools have limited clinical suitability due to potential immunogenic risk associated with the use of foreign proteins as well as limited delivery potential from requiring large genetic payloads. While proteinlevel circuits may offer rapid, compact delivery encoded on a single transcript, they typically are designed using viral proteases to limit crosstalk with the human proteome. In this thesis, I investigate the use of a highly specific human protease, renin, as a tool to build orthogonalized circuits using human components. Using a combination of localization strategies and structure-guided mutagenesis, we orthogonalize renin and its protease cut-site from the human body. Additionally, we engineer a variety of secreted signals, protease-activated receptors, and cleavable degradation motifs that respond to renin activity. Overall, I will present a variety of architectures that an orthogonalized renin can enable to control intracellular communication using human proteins and their use in the support of a variety of cellular therapeutics.