Charge-Transfer-Driven Enantioselective Surface-Enhanced Raman Scattering on a ZIF-8/ZnS Heterojunction: A Chiral-Label-Free Biosensor for Quantification of Urinary Lactate Enantiomeric Excess

Abnormal lactic acid (LA) enantiomeric excess (ee) in biofluids is closely associated with various intestinal diseases. Here, we report a chiral-label-free nonplasmonic surface-enhanced Raman scattering (SERS) platform using a ZIF-8/ZnS heterojunction that enables direct quantification of LA enantiomers and their ee values in raw human urine through a charge-transfer-driven chiral recognition mechanism. Our findings indicate that an enantioselective hydrogen bonding between 4-mercaptopyridine (4-MPy) probes and LA enantiomers induces differential charge-transfer effects within the ZIF-8/ZnS@4-MPy system, evidenced by the selective enhancement of specific vibrational modes in the SERS spectra of 4-MPy and enantiomer-specific changes in the fluorescence lifetime of ZnS. This innovative system integrates signal amplification and stereoselectivity without the use of noble metals or chiral modifiers, overcoming critical limitations associated with the complexity of preparing chiral plasmonic substrates. The platform achieves ultrasensitive detection limits (10 nM), linear response to ee values (<i>R</i>² = 0.98), high measurement precision (RSD < 8.28%, <i>n</i> = 20), long-term stability (28-day), and clinical-grade accuracy against enzymatic assays (RMSEP = 1.97). This work presents an efficient, noninvasive method for the analysis of chiral metabolites in urine, while establishing a novel direction for plasmon-free SERS chiral sensing.