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Accurate quantification of structurally similar metabolites as biomarkers in biofluids has remained a longstanding challenge. Here, we report a semiconductor-organic hybrid interface (ZrS2@ZrOx-C16) with a triple-gated molecular recognition environment for high-specificity detection of lysophosphatidylcholine (16:0) (LysoPC (16:0)), which is identified as a potential biomarker associated with aging and cognitive decline. Through integrating phosphocholine-selective Zr–O–P coordination, chain-length-matched hydrophobic free-energy minimization, and a dual-resonant charge-transfer pathway, ZrS2@ZrOx-C16 affords molecular-level discrimination among lysophospholipids with nearly identical chemical structures, enabling amplified and selective quantitative Raman signals. Coupled with machine-learning extraction of Raman fingerprints, ZrS2@ZrOx-C16 achieves rapid, label-free quantification with an accuracy of R2 = 0.999 across human and mouse serum samples, allowing precise mapping of LysoPC (16:0) deficits as a biomarker and therapeutic target across aging, Alzheimer’s disease, and perioperative neurocognitive impairment. This work establishes a framework for precision lipid analytics and high-selectivity metabolic sensing, enabling mechanistic insights in neurometabolic biology.
Huang et al. (Tue,) studied this question.