Cellular communication through the bilayer of biological membranes is mediated by signal transduction and is essential for life. The high complexity of this process makes it one of the major challenges in terms of cell mimicry. A key component in signal transduction is the natural receptors found on the cell surface. Herein, we present the novel design of membrane anchored, fully synthetic receptors (Figure 1A), namely an apoptosis inducing receptor (AIR) and an enzyme activating receptor (EAR). The mechanism of artificial signal transduction is triggered extracellularly by an enzymatic cleavage of the trigger moiety that entails the degradation of a self-immolative linker (SIL) leading to internal release of an effector molecule (Figure 1B). The effector molecule released from the AIR is a potent drug establishing it as a synthetic “kill switch” (Figure 1B 3.1), that demonstrates controlled enzyme triggered deactivation of engineered cells in 3D cell cultured spheroids (Figure 1C). A potential valuable tool against an adverse immune response in cell-based therapy. To advance the scope of fully artificial signal transduction even further, triggering of the EAR leads to the release of a small biological zymogen activating molecule, continuing the signaling cascade (Figure 1B, 3.2). Together these novel synthetic receptors demonstrate a major advancement in the field of artificial signal transduction and encourage the intriguing future of cell mimicry.

Artificial signal transduction over biological membranes

ACS Spring 2022

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