Synthetic macromolecular switches for precision control of therapeutic cell functions

Cells rely on complex molecular networks to perceive and process external and internal signals into tailored responses. These cellular abilities can be augmented and modified by integrating artificial gene circuitry for the engineering of cell-based therapeutics. In this Review, we outline the engineering principles that govern the design of synthetic gene networks, highlighting how the sensitivity, detection range and specificity of synthetic gene networks can be optimized for in vivo functionality. In particular, we examine synthetic molecular modules, including transcriptionally regulated, translationally regulated and post-translationally regulated circuits, that enable tailored adjustments in therapeutic cell functions based on dynamic disease-state cues, or that can be remotely controlled using clinically compatible external molecular or physical signals. Furthermore, we explore the potential of multi-input regulatable logic-gated programs to enhance the efficacy and safety of engineered cell immunotherapies for cancer treatment, and highlight the application of synthetic gene circuits for gene therapy and the design of therapeutic microbes. Finally, we examine how synthetic-biology-inspired therapies may benefit from evolving genome engineering technologies and synergy with artificial intelligence.