Volume‐Enhanced Raman Scattering Detection of Viruses

Abstract Virus detection and analysis are of critical importance in biological fields and medicine. Surface‐enhanced Raman scattering (SERS) has shown great promise in small molecule and even single molecule detection, and can provide fingerprint signals of molecules. Despite the powerful detection capabilities of SERS, the size discrepancy between the SERS “hot spots” (generally, <10 nm) and viruses (usually, sub‐100 nm) yields poor detection reliability of viruses. Inspired by the concept of molecular imprinting, a volume‐enhanced Raman scattering (VERS) substrate composed of hollow nanocones at the bottom of microbowls (HNCMB) is developed. The hollow nanocones of the resulting VERS substrates serve a twofold purpose: 1) extending the region of Raman signal enhancement from the nanocone surface (e.g., surface “hot spots”) to the hollow area within the cone (e.g., volume “hot spots”)—a novel method of Raman signal enhancement, and 2) directing analyte such as viruses of a wide range of sizes to those VERS “hot spots” while simultaneously increasing the surface area contributing to SERS. Using HNCMB VERS substrates, greatly improved Raman signals of single viruses are demonstrated, an achievement with important implications in disease diagnostics and monitoring, biomedical fields, as well as in clinical treatment.