Engineering Protein Circuits for Cellular Control and Precision Immunotherapy

Protein structural complexity confers responsiveness and modularity, allowing proteins to act as control modules in biomolecular circuitry. Protein engineering that commandeers native cell signaling and central dogma functions has led to the development of cell therapies, specialized biosensors, and a deeper understanding of cellular mechanisms. In this review, we examine how protein control modules command circuitry with therapeutic functionality across cellular spatial levels. Extracellularly, signal proteins such as antibodies and cytokines can provide either binary or gradient-sensitive detection of environmental features. Extracellular proteins also serve as inputs to synthetic receptors that transmit signals across membranes, rapidly linking environmental cues to intracellular action. Inside the cell, protein control modules are engineered from central dogma components to bind nucleic acids, creating gene circuits that influence transcription, translation, and nucleic acid processing, and ultimately regulate protein expression. This review covers circuitry platforms and immunoengineering applications across spatial levels, focusing on innovation from 2016 to 2026. With continued development, synthetic biocircuits can serve as a platform for creating next-generation “smart” therapeutics and ultimately for engineering immunity.