Sulfur-Substituted Hemicyanine Nanosensors Enable Noninvasive Evaluation of Diabetic Liver Dysfunction through Cysteine Detection

Diabetic liver dysfunction is characterized by oxidative stress and disrupted cysteine (Cys) metabolism, but noninvasive monitoring tools remain lacking. Here, we developed a sulfur-substituted hemicyanine-based nanosensor (S-Nanoprobe) that generates enhanced near-infrared photoacoustic signals upon selective Cys recognition. The sulfur substitution improved vibrational relaxation efficiency, yielding a stronger photoacoustic signal than oxygen-substituted analogs, with a 0.12 μM detection limit and exceptional selectivity (no interference from homocysteine or glutathione). In streptozotocin-induced diabetic mice, the probe enabled noninvasive tracking of hepatic Cys dynamics, revealing significant Cys accumulation in diabetic mice (higher than controls), while metformin-treated mice showed intermediate levels. Histopathological analysis confirmed correlations between Cys levels and liver injury severity. This technology provides a novel molecular imaging approach for early assessment of diabetic liver dysfunction and establishes a versatile platform for studying thiol metabolism. The probe’s high specificity, biocompatibility, and signal-to-noise ratio make it promising for translational applications in metabolic disease monitoring.