SERS biodetection SERS-Based Diagnosis and Biodetection Ramo ´n A. Alvarez-Puebla * and Luis M. Liz-Marza ´n* Surface-enhanced Raman scattering (SERS) spectroscopy is one of the most powerful analytical techniques for identification of molecular species, with the potential to reach single-molecule detection under ambient conditions. This Concept article presents a brief introduction and discussion of both recent advances and limitations of SERS in the context of diagnosis and biodetection, ranging from direct sensing to the use of encoded nanoparticles, in particular focusing on ultradetection of relevant bioanalytes, rapid diagnosis of diseases, marking of organelles within individual cells, and non-invasive tagging of anomalous tissues in living animals. 1. Introduction The prompt, sensitive and accurate response of analytical techniques to resolve detection issues, in particular those related with health, has always been a key aspect in (applied) science. To date, many analytical tools based on different physical, chemical, and biological phenomena have been developed for structural characterization of biomolecules, biosensing, biodiagnosis, and biomedical imaging, including mass spectrometry, fluorescence spectroscopy, and techniques based on specific recognition events such as enzyme-linked immunosorbent assay (ELISA), fluorescence immunoassay (FIA), or radioimmunoassay (RIA). However, none of these techniques has been able so far to fulfill all the expectations of modern biomedicine because they are time consuming, have relatively low detection limits, and/or require special environ- ments, far away from biological conditions. Recently, mainly driven by the significant advances in optics, laser technology, detection devices, and nanofabrication, surface-enhanced Raman scattering (SERS) has arisen as a versatile tool that offers sensitivity, together with structural information in biological media. SERS spectroscopy is one of the most powerful analytical techniques for identification of molecular species, with the potential of reaching single-molecule detection under ambient conditions. [1] SERS provides complete vibrational information of the molecular system under study and, since the output is essentially a Raman scattering spectrum, it is highly sensitive toward conformational changes. [2] On the other hand, and due to surface selection rules, which further increase the intensity of the vibrational modes perpendicular to the surface while maintaining parallel modes constant, the orientation of the molecule on a given support can be readily extracted from the acquired spectrum. [3,4] All of these features together make SERS not only the tool of choice for a number of analytical problems comprising molecules but also an extremely inter- esting technique for the study of biomolecules, pathogens, and disease markers. SERS is purely a nanoscale effect, deriving from localized surface plasmon resonances (LSPR) in nanostructured metals, which give rise to huge electromagnetic fields at the nanometal surface. [5] The enhancement of the Raman signal is mainly achieved by coupling of the vibrational modes of the analyte molecule with the electromagnetic field (LSPR) generated at a metallic nanostructure, usually made of gold or silver, upon excitation with light of appropriate energy. SERS can be carried out using the LSPR from individual nanoparticles, for example, in a colloidal suspension, which is known as average SERS. However, particle aggregates have been found to provide much higher enhancement due to coupling between the LSPRs of the different particles within the aggregate, resulting in a significantly higher electromagnetic field at certain regions concepts [  ] Dr. R. A. Alvarez-Puebla, Prof. L. M. Liz-Marza ´n Departamento de Quimica-Fisica and Unidad Asociada CSIC-Universidade de Vigo 36310 Vigo (Spain) E-mail: ramon.alvarez@uvigo.es; lmarzan@uvigo.es DOI: 10.1002/smll.200901820 Keywords:  biodetection  nanoparticles  sensing  SERS  surface plasmon resonance 604 ß 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim small 2010, 6, No. 5, 604–610