## 3 Results and Discussion  
As depicted in Figure 1, our proposed Raman-based detection strategy to identify virus particles rests on a highly specific sample preparation scheme. To selectively enrich the beads' surface with virus particles of the virus type to be detected, a specific recognition element is required. Instead of employing an antibody, we decided to exploit the ACE2 receptor that SARS-CoV-2 uses for attaching itself to the host's cells [31; 32]. As is the case in all coronaviruses, SARS-CoV-2 uses its spike glycoprotein (S protein) for binding to the cellular receptors [33]. The particularly specific binding between the viral S protein and the host receptor is also responsible for the efficient transmission of SARS-CoV-2 among humans [34]. However, this is only the first step of the viral entry into the cells. The trimeric S protein has a clove-like structure, with a S1 (head) and a S2 (stem) subunit. While the S1 unit contains the receptor binding motif, the S2 unit is responsible for the fusion with the host cell membrane, after which the nucleic acid is inserted into the cells. For this process, proteases such as furin or transmembrane serine protease 2 (TMPRSS2) are required for cleaving the S protein at distinct sites [35]. Employing the receptor instead of an antibody as the recognition element is advantageous from our perspective as viruses are constantly subject to mutation, and therefore alter their protein structure. Accordingly, certain mutations and/or recombination will cause an antibody-based assay to fail because the target element is poorly or no longer recognized. By using the very same element as the capture probe that the virus needs to infect the cells, such an issue will most likely not occur, even when the virus mutates and recombines [36]. As mentioned before, we aspire to detect the virus particles with conventional Raman spectroscopy. Due to the small size of the virus and potentially low concentrations, we needed to enrich them before conducting the actual measurements. To that end, we employed magnetic beads-micrometer-sized polymer particles with magnetic nanoparticles embedded in them. They are commercially available with various surface modifications, enabling different strategies for functionalization. We chose streptavidin-modified magnetic beads as their further decoration with capture elements is very easy and well reproducible. The immobilization of the capture probes on such surfaces exploits the very strong interaction between the protein avidin or streptavidin (an avidin protein produced by bacteria of the genus _Streptomyces_) and the vitamin biotin. With a dissociation constant of K = 10\({}^{-15}\) M, this biological interaction is the strongest known non-covalent interaction [37]. Further advantages are the relatively high robustness in terms of the pH, temperature and solvents [38]. Many biomolecules can be purchased with biotin modification or, alternatively, coupling kits are available, which also allow non-experts to perform a biotinylation. In addition, applying the proposed sample preparation concept comes with very few obstacles. In our study, we used a prefabricated biotinylated ACE2 receptor. The scheme in Figure 2 depicts the individual steps of the sample preparation procedure. In the first step, the ACE2-functionalized particles are added to the sample, which might contain SARS-CoV-2, another virus (for example Influenza A virus), other microorganisms or no pathogens at all. During the incubation time, the SARS-CoV-2 particles will attach themselves to the bead surface due to the spike protein receptor, with a reported binding constant ranging between 0.11 nM [39] and 14.7 nM [40]. In order to achieve the selective enrichment of SARS-CoV-2, washing steps are implemented, where the solid phase (the magnetic particles) is separated from the liquid phase (the supernatant). During these washing steps, all viruses that are not immobilized on the bead surface will be removed.