Because of the high sensitivity, molecular specificity, and non-invasive sampling technique, surface enhanced Raman scattering (SERS) is one of the most powerful analytical techniques. Additionally, its low interference from water makes SERS uniquely effective for biological sensing. In the last decade, the emergence of life-threatening pathogens and debilitating diseases has outpaced the development of treatments. Detection and monitoring have become the first guard approach to containing the spread of deadly infections such as Ebola, H1N1, and SARS-CoV-2. As a result, recent SERS research has heavily focused on studying biological processes and point of care diagnostics.The choice of the nanostructure of the SERS substrate determines its localized surface plasmon resonance which directly contributes to the overall SERS enhancement. Hollow nanostructures are advantages as SERS substrates due to their highly tunable optical properties, which arise from varying the outer diameter to shell thickness. However, hollow nanoparticles have been underexplored due to a more complex synthesis needed to control their physical dimensions. The work in this dissertation explores using hollow gold nanospheres (HGNs) as a template to synthesize rugose hollow nanostructures. HGNs enabled fine control over the hollow (void space) core. However, isotropic geometry yields a single plasmon mode limiting the number of hot spots for SERS enhancement. Rugose nanostructures have improved electric field strength as compared to smooth nanoparticles. More specifically, spiny nanostructures have better electron confinement at their tips. A multibranched structure has an increased number of hot spots. Multibranched hollow gold nanostructures were synthesized using hollow gold nanospheres as a seed particle. Chapter 1 introduces general concepts of plasmonics applied to Raman spectroscopy, specifically how the nanostructure of noble metals influences the localized surface plasmon resonance. The latter part of chapter 1 discusses the characterization of metal nanoparticles through absorption spectroscopy and electron microscopy. Chapter 2 highlights the use of hollow gold nanostars and PEG-based conjugation to overcome the difficulty of detecting amyloid beta 1-14. As a result, we increased our understanding of the parameters needed to detect low Raman scatterers in aqueous media. The key findings were that hollow gold nanostars enable improved SERS enhancement compared to hollow gold nanospheres and solid gold nanostars. The analytical enhancement factor of the hollow gold nanostars was 1.29 x 109 for the 1367 cm-1 peak in R6G was shown to be 11.5 times increased compared to hollow gold nanospheres. Chapter 3 focuses on developing a new method to detect the SARS-CoV-2 S1 spike protein and the anti-SARS-CoV-2 antibodies by anchoring the his-tagged spike protein to a multibranched gold nanoshell for detection via SERS. Multibranched gold nanoshells were prepared using HAuCl4, AgNO3, and ascorbic acid to improve the optical and morphological properties of smooth ~150 nm gold nanoshells for detecting proteins. The multibranched gold nanoshells were gently mixed with a his-tagged SARS-CoV-2 S1 spike protein, purified, and mixed with Anti-SARS-CoV-2 monoclonal antibodies. Raman and SERS measurements of the spike protein and monoclonal antibody with a histidine tag showed a significant increase in peak intensity compared to samples without histidine. Enhanced SERS peaks from the spike protein at 1079, 1178, and 1592 cm-1 are attributed to δ =N-H, νC-N, νC=C, respectively. Enhanced peaks from the Anti-SARS-CoV-2 monoclonal antibody at 861, 1205, 1454, and 1630 cm-1 can be assigned to νN-H, νC-C, C-H def, and νC=O associated with the phenylalanine and tyrosine rich region closest to the binding sites on mAb. Chapter 4 discusses the work to apply fiber-enhanced SERS to monitor the repair process of a self-healing wastewater purification membrane. The use of a SERS substrate with hollow core photonic crystal fiber (HCPCF) as a waveguide increased the signal intensity for major distinguishing hydrocarbon tail peaks at 1436cm-1 (CH2 bend) and 1296cm-1 (CH2 twist) by 1.5 and 2x as compared to SERS alone. The increase in signal for lower intensity C-C peaks such as 1157cm-1 was 14x compared to SERS alone. The results show that SERS coupled with a waveguide can enable highly sensitive in situ measurements.