Specific peptide enrichment strategies for neuropsychiatric disorders: From material design to diagnostic applications

Peptide biomarkers play critical roles in the diagnosis and monitoring of psychiatric disorders, reflecting alterations in synaptic transmission, neuroinflammation, stress signaling, and intracellular phosphorylation networks. However, the ultra‐low abundance, structural heterogeneity, and diverse post‐translational modifications of endogenous peptides hinder their reliable detection in complex biological matrices. Specific peptide enrichment‐enabled peptidomics has therefore emerged as an essential analytical strategy to enhance sensitivity, selectivity, and quantitative robustness in neuropsychiatric biomarker research. This review systematically summarizes recent methodological advances in specific peptide enrichment strategies, including metal‐based systems, magnetic oxide platforms, functional polymer materials (molecularly imprinted polymers, boronate‐affinity polymers, and organic‐inorganic hybrids), and antibody‐based approaches. We discuss their underlying recognition mechanisms, structural design principles, and compatibility with high‐throughput and automated workflows. Importantly, we highlight the translational applications of enrichment‐enabled peptidomics in major psychiatric disorders, including Alzheimer's disease, bipolar disorder, major depressive disorder, schizophrenia, generalized anxiety disorder, and post‐traumatic stress disorder. Enrichment‐enabled strategies facilitate ultrasensitive profiling of phosphopeptides, glycopeptides, neuropeptides, and variant peptides in brain tissues and peripheral biofluids, supporting early diagnosis, disease stratification, and therapeutic monitoring. Despite substantial progress, challenges remain in material reproducibility, multiplexed modification analysis, and large‐scale clinical validation. Continued advances in multifunctional materials, microfluidic integration, and artificial intelligence‐assisted multi‐omics analysis are expected to accelerate precision diagnostics in psychiatric disorders.