Nonlinear Optical Detection of β2-Microglobulin Exploiting Graphene-Enhanced Terahertz Third-Harmonic Generation. Sensors 2026, 26, 6779. https://doi.org/10.3390/s26216779

β2-Microglobulin (β2M) is a crucial biomarker associated with kidney dysfunction, dialysis-related amyloidosis, and inflammatory disorders, encouraging the development of sensitive sensing platforms. Here, we suggest a nonlinear terahertz (THz) sensing platform based on graphene-enhanced third-harmonic generation (THG) for β2M detection. In contrast with conventional graphene plasmonic sensors that depend on linear resonance shifts, the proposed approach investigates the strong dependence of graphene’s nonlinear optical response on its Fermi energy. Adsorption of charged β2M molecules changes graphene’s carrier concentration and Fermi energy, resulting in a detectable signal in the THG response. The sensor includes periodically patterned graphene microribbons integrated with a gold substrate with a thin Kerr nonlinear dielectric spacer, forming a resonant metasurface with strong THz field confinement. The combined impacts of graphene plasmonic resonances and cavity-enhanced field localization significantly increase THG at relatively low incident intensities. The impact of graphene Fermi energy, dielectric thickness, and excitation intensity on the sensing performance are systematically investigated. The simulation results predict concentration-dependent shifts in the THG spectral response and intensity, with increasing β2M concentration producing a progressive shift toward higher frequencies. The simulations predict β2M detection at concentrations as low as 0.0001 g/L, achieving a sensitivity of 971 THz·L/g and a figure of merit (FOM) of 1706 L/g. These theoretical results represent the potential of graphene-enhanced THG metasurfaces for sensitive, tunable, and compact THz biosensing and biomedical diagnostics.