Surface enhance Raman spectroscopy (SERS) as an emerging advanced trace analysis technique with ultra-sensitive and fingerprint-free features, achieves fast and non-invasive detection combined with microfluidic chip in optical fluid detection. SERS signals with the features of stability, reproduction, highintensity and high-sensitivity are the prerequisites for obtaining valid bio-sensing information. A number of investigations demonstrate that noble metal nanoparticle aggregates of controllability or nanoparticle arrays are crucial for generating the above SERS signals. The research progress of certain aspects is summarized in this article, which includes the enhancement and reappearance of high-sensitivity SERS signals by using metal nanoparticle aggregates of controllability and solid SERS active substrate formed by utilizing electric and magnetic fields, the increasing effect of solid SERS substrate on body surface area, and the application of SERS biosensor in clinical immunoassay. This review provides references to further study on the mechanism of reproduction and enhancement of SERS signal by noble metal nanoparticles, especially the application of SERS bio-sensor, and offers scientific evidence for optimizedesign on solid SERS active substrates to achieve portable and intelligent SERS bio-sensor system.