Gold-Functionalized Multilayer Heterojunction Microarchitectures Enable High-Fidelity Serum Metabolite Profiling for...

Skin cancer is among the most prevalent malignancies worldwide, with non-melanoma types ranking among the top five and melanoma characterized by high lethality. Psoriasis, although non-malignant, imposes a substantial physical and psychological burden. Accurate and timely detection is crucial for improving clinical outcomes. Serum metabolites, as sensitive indicators of systemic physiology, represent promising noninvasive biomarkers. Here, we developed gold-modified rose-like multilayer heterojunctions (G-RMHJ) as an efficient matrix for laser desorption/ionization mass spectrometry (LDI-MS). The hierarchical multilayer architecture and heterojunction interfaces, combined with gold functionalization, synergistically enhance light absorption, interfacial energy transfer, and ionization efficiency, enabling sensitive and reproducible serum metabolite detection. In a cohort of 130 skin cancer and 23 psoriasis patients together with 218 healthy controls (HC), G-RMHJ-assisted LDI-MS yielded robust serum metabolic fingerprints, and machine learning models built on these data achieved 100% test-set accuracy for classifying patients vs. HC. Eight discriminative metabolites were identified that reliably differentiated four types of diseases from HC, with area under the curve values ranging from 0.933 to 1.000. This work demonstrates how hierarchical microstructured heterojunctions can directly translate materials-level design into enhanced bioanalytical performance, providing a generalizable and noninvasive framework for serum metabolomics-based disease classification and skin cancer subtype identification.