The detection of circulating disease biomarkers in bodily fluids, also known as liquid biopsy, has taken important strides toward the implementation of personalized medicine. However, it still suffers from low sensitivity and high costs, which render its clinical implementation not practical or affordable. In particular, the identification and quantification of oligonucleotide biomarkers is hampered by the need to employ long- and short-read sequencing tools that are expensive, require highly trained personnel, and are prone to error. Nonetheless, the recent clinical breakthroughs demonstrating the importance of detecting cancerous or viral biomarker to susceptibility, onset, and aggressiveness of the disease, motivate the need for further research that could render their detection simpler, cheaper, and thus more widely available. By leveraging the intrinsic amplification capability of surface enhanced Raman scattering (SERS), in ANFIBIO I will address the issues of low sensitivity and high costs by combining plasmonic nanoparticles synthesized ad hoc to maximize SERS signal amplification with direct SERS sensing and machine learning tools for the rapid analysis of the complex spectral responses obtained by screening bodily fluids for specific target biomarkers. I will focus in particular on prostate cancer (PCa) DNA and influenza A viral (IAV) RNA in blood, urine, and saliva, to quantify and correlate their amounts to those detected in tissues and cells. At completion, the proposed work will deliver a breakthrough sensing technology capable of detecting and quantifying cancerous and viral biomarkers in bodily fluids, with minimal sample pretreatment, no target amplification, and that uses SERS as novel and reliable transduction mechanism with distinct advantages over those currently employed. Furthermore, the fundamental insight garnered will likely assess the feasibility of using direct SERS sensing to develop beyond-third generation sequencing technologies.