A Molecular Logic Gate for Developing “AND” Logic Probes and the Application in Hepatopathy Differentiation

[Image: see text] Accurate diagnosis and therapy are challenging because most diseases lack a single biomarker that distinguishes them from other disorders. A solution would enhance targeting accuracy by using AND-gated combinations of two disease-associated stimuli. Here, we report a novel “AND” molecular logic gate, enabling a double-controlled release of intact functional molecules. Benefiting from a significant difference in intramolecular cyclization rate, cargo release occurs notably faster with the presence of both stimuli. According to this finding, several AND logic probes have been developed that respond to a broad scope of stimuli and show remarkably improved signal-to-background contrast compared to those of monoresponsive probes. In addition, an AND logic probe that is responsive to monoamine oxidase (MAO) and leucine aminopeptidase (LAP) has been constructed for hepatopathy diagnosis. It works efficiently in living cells and mouse models. Of note, this probe can successfully differentiate cirrhotic from hepatitis B by testing the blood samples from patients.