Synergistic Effects in a Homochiral Metal−Organic Framework Enable Enhanced Enantiomeric Discrimination and Ultrasensitive Detection of Disulfide-Containing Biomarkers

The rational design of chiral interfaces that emulate the sophisticated recognition of biological systems remains a persistent challenge in sensing, demanding molecular recognition with high specificity and affinity. Progress in this area is crucial for advancing sensing capabilities, particularly in the precise quantification of biomarkers, including urinary L-cystine for human cystinuria and cellular glutathione disulfide (GSSG) for vivo oxidative stress. Herein, we report a homochiral metal-organic framework (MOF), <b>Zn-TMTyrBa</b>, engineered as an electrochemical sensing platform for the specific detection of L-cystine and GSSG. By leveraging synergistically integrated binding sites, this MOF achieves ultra-low detection limits (46.1 pM for L-cystine and 0.12 pM for GSSG) and unprecedented chiral selectivity between cystine enantiomers (<i>I</i>_L/<i>I</i>_D = 55.2; Δ<i>E</i> = 200 mV). The sensor demonstrates reliable quantitative capability for target analytes in complex matrices, including racemic mixtures, artificial cerebrospinal fluid, and fetal bovine serum, and has been applied to quantify L-cystine in human urine, yielding results that fall within the typical physiological range for healthy individuals. Mechanistic studies reveal that the superior performance arises from a synergy between the configurational match of the chiral microenvironment of the MOF with the target analytes and the complementary specific binding interactions of its integrated multifunctional groups with corresponding analyte moieties. This work establishes a viable strategy that utilizes multisite synergy in MOFs to significantly enhance sensing specificity, thereby providing new insights for the design of high-performance chiral sensing interfaces.