Saliva Liquid Biopsy for Detection of Oral and Systemic Diseases.

Saliva has emerged as a compelling liquid biopsy for the non-invasive diagnosis and monitoring of both oral and systemic diseases. Secreted by major and minor salivary glands and enriched by gingival crevicular fluid, epithelial turnover, immune mediators, microbial products, and plasma-derived constituents, saliva reflects a biologically integrated interface between local oral environments and systemic physiology. This dual origin enables detection of disease-associated signals across multiple molecular layers, including extracellular RNA, cell-free DNA, genomic and epigenetic material, proteins, metabolites, microbial signatures, and hormones. Advances in high-throughput sequencing, mass spectrometry, and ultrasensitive immunoassays have revealed that salivary analytes can capture dynamic pathological processes ranging from periodontal inflammation and dental caries to oral and head and neck cancers, as well as systemic conditions such as non-oral cancers and autoimmune, cardiometabolic, infectious, endocrine, and neurodegenerative diseases. In particular, extracellular vesicle-encapsulated RNA, cfDNA fragmentomics, and methylation patterns have expanded the diagnostic reach of saliva beyond conventional protein-based biomarkers, while integrated multi-omics approaches increasingly improve diagnostic performance. Despite this progress, clinical translation remains constrained by biological complexity, including variable glandular contributions, oral microbiome interactions, and pre-analytical variability in collection and processing. Emerging point-of-care technologies, microfluidic platforms, and artificial intelligence-driven multi-omic integration are beginning to address these limitations, enabling higher analytical sensitivity and improved disease stratification. Regulatory pathways, including in vitro diagnostic frameworks and laboratory-developed test structures, are progressively accommodating salivary assays, as demonstrated during the COVID-19 pandemic. However, widespread clinical adoption will require rigorous standardization, large-scale validation, and demonstration of clinical utility. Together, saliva-based liquid biopsy represents a rapidly evolving diagnostic paradigm with the potential to shift disease detection towards earlier, minimally invasive, and data-rich precision medicine approaches across dentistry and systemic healthcare.