Silicon nanowires (Si NWs) are considered an outstanding material for several applications. We have realized quantum-confined and room-temperature luminescent Si NWs. These Si NWs exhibit a high-aspect ratio, and high sensitive and selective label-free detection has been demonstrated for proteins, small extracellular vesicles, and DNAs. The realization of a SARS-CoV-2 Si NW sensor able to detect a few virus copies and remain unaffected by the variant (such as Omicron) is reported, paving the way for new, cheap, optical label-free devices for the primary health care diagnosis with an industrially compatible approach.