Molecule-Level Interpretable SERS Diagnosis of Prostate Cancer via Prostatic Fluid Metabolites and Extracellular Vesicles

Prostate cancer (PCa) remains a major global health burden, yet current screening tools often lead to overdiagnosis due to low specificity, highlighting the urgent need for more precise diagnostic approaches. Prostatic fluid (PSF) represents a promising but underexplored biofluid with exceptional diagnostic potential due to its direct contact with the PCa microenvironment. Here, we employed molecule-level interpretable surface-enhanced Raman spectroscopy (SERS) to comprehensively investigate PCa-associated alterations in two PSF components including metabolites and small extracellular vesicles (sEVs) and explored their potential interrelations via correlation analysis. Through molecule-resolvable SERS spectral set (MORE SERSome) technique, we identified ergothioneine and deoxyguanosine as differential metabolites between PCa and benign prostatic hyperplasia patients. We further constructed a fusion diagnostic model by integrating metabolites and sEVs information. The fusion model significantly outperformed the diagnostic accuracy by applying any single component, suggesting diagnostic complementarity between PSF metabolites and sEVs. Integration with clinical variables such as age and plasma prostate-specific antigen concentration further enhanced performance with the area under the curve as high as 0.93 for PCa diagnosis, substantially surpassing existing screening methods. These findings strengthen the importance of in-depth analysis of specific PSF components and further promise the potential of SERS-based PSF profiling as a noninvasive strategy for PCa diagnosis and biopsy guidance.