Emerging Salivary Exosome Nanodiagnostics for Early Oral Squamous Cell Carcinoma: Platforms, Biomarkers, and Future Perspectives.

Early oral squamous cell carcinoma (OSCC) is frequently missed because conventional imaging and biopsy are poorly suited to detect subtle, preclinical molecular changes. Emerging salivary exosome nanodiagnostics aims to convert an anatomically proximal, information-rich nanoscale biospecimen into quantitative and repeatable readouts for screening and longitudinal monitoring. Clinical translation, however, is constrained by four bottlenecks: (i) pre-analytical variability in saliva collection, processing, and storage; (ii) yield-purity trade-offs during vesicle enrichment; (iii) low-abundance tumor-derived signals masked by abundant background vesicles; and (iv) biomarker heterogeneity that limits robustness across cohorts. Here, we integrate the landscape of salivary exosomal biomarkers (nucleic acids, proteins, and other cargo) and synthesize nanotechnology-enabled solutions that directly address these barriers, including microfluidic and affinity-based enrichment, nucleic-acid amplification circuits (eg, RCA, HCR, CHA) for signal gain, and optical/electrochemical transduction (eg, SPR, SERS) compatible with microliter-scale samples. Beyond listing platforms, we propose a unifying framework: co-design capture and readout to preserve biological specificity, match biomarker modality to detection physics, and prioritize multi-marker panels with transparent analytical benchmarks. Finally, we outline a translational roadmap spanning standardization, reproducibility, prospective multicenter validation, manufacturability, and regulatory readiness to accelerate clinically actionable early OSCC detection.