Scalable optical metasurfaces for ultrasensitive, label-free and real-time biosensing

Novel biosensors based on optical metasurfaces offer superior sensing performance in compact form factors, with transformative potential spanning biomedical research, clinical diagnostics and drug screening. However, their translation to real-world applications is hindered by a strong reliance on sophisticated and expensive top-down nanolithographic techniques with limited accessibility and low throughput. Here, we demonstrate scalable, high-throughput metasurfaces with optofluidic integration for label-free biosensing, exemplified by high-quality large-area gold nanohole arrays via nanosphere self-assembly lithography. Through comprehensive resonance analysis, we identified a surface plasmon polariton–Bloch wave mode that is both highly sensitive and experimentally accessible using cost-effective setups with incoherent visible light. Moreover, to improve the mass transport and analyte capture, we optimized the functionalization scheme, microfluidic design, and the metasurface placement within the microfluidic channel. The versatile meta-sensors were demonstrated with a broad range of targets, from biomolecules such as immunoglobulin G, streptavidin, to streptavidin-coated nanoparticles, which mimic virus particles and extracellular vesicles. By holistically improving the nanopatterning quality, functionalization efficiency and optofluidic integration, we achieved an experimental refractometric sensitivity of 498 nm/refractive index unit at 736 nm wavelength, a limit of detection of 0.17 ng/mL for biomolecules and ≲1 × 107 /mL for nanoparticles. These scalable, cost-effective meta-sensors deliver sensing performance, dynamic range, and stability comparable to, or even surpass, those of state-of-the-art devices fabricated using top-down lithography, thereby bridging the gap toward practical applications.