Assay technologies capable of detecting biomarker concentrations in unprocessed whole blood samples are fundamental for applications in medical diagnostics. SERS nano-tags integrated fiber-optic biosensor (FOB) was realized for the first time for in situ immunoassay in whole blood. The reliability and sensitivity of this method rely, in a large extent, on the quality and properties of the SERS nano-tags. The constructed silica coated Ag SERS nano-tags as labels were used in a rapid and specific in situ FOB immune sensor to detect alpha fetoprotein (AFP) in unprocessed blood samples. Preliminary results of in vivo and in situ dynamic observation of AFP of whole blood in wistar rat highlight the power of this new method.