Human C-reactive protein (CRP), an early clinical indicator of infectious or inflammatory conditions has been recently identified as a key biomarker associated with the development of COVID-19. The rapid and accurate determination of CRP level in blood serum is an urgent need to predict timely the risk of disease worsening. This project aims to design a new aptamer-modified plasmonic nanobiosensor able to offer relevant solutions for CRP determination with high sensitivity, high specificity and portability. The concept will be demonstrated using colloidal plasmonic nanoparticles (PNPs) as the sensing units, a component for surface-enhanced Raman scattering (SERS) detection (Raman reporters) and aptamers as the biorecognition elements. The aptamers attached onto the metallic surface will be used to recognize CRP, while PNPs will be exploited as sensitive optical transducers in three ways: (1) as colorimetric, (2) as SERS and (3) as thermoplasmonic (thermometric) indicators. The three mechanisms of detection will mutually validate each other, thus improving the accuracy and reliability of CRP determination. Due to the simplicity of the assays, robustness of molecular bioreceptors, high portability for detection (colorimetric with naked eyes, SERS with a portable Raman spectrometer, thermoplasmonic with a portable digital thermometer) the proposed strategy offers an attractive perspective in designing portable nanosensors for rapid determination of various diseases biomarkers.