Both resonance modes exhibit a tight confi nement of the exponentially decaying electromagnetic fi eld. Hence the optical properties can be highly sensitive to small changes of the refractive index (RI) in close proximity to the metal surface. A change of the effective RI resulting from molecular binding events at the surface of the SP-based sensor, therefore, can be directly detected in real time as the changes in optical intensity, [13][14][15][16][17] wavelength, [18][19][20] or angle. [ 21,22 ] In conventional surface plasmon resonance (SPR) detectors, such as the commercially available BIAcore, light is coupled into SPP modes on a fl at, continuous gold fi lm via a prism-based coupling, known as the Kreschmann confi guration. [ 23 ] This has proved to be a highly effective tool in clinical diagnosis, but the cumbersome prism coupling remains diffi cult to integrate into cost-effective, high-throughput, and portable devices for rapid bioanalytical measurements. Therefore, plamonic sensors that do not require any bulky coupling optics are highly desired.From this point of view, nanostructured free-electron metals are of increasing interest. For one thing, they can solve the momentum mismatch between photons and SPs, [ 24 ] which makes them be resonantly excited by light without the need for any couplers; for another, continuing advances in nanoparticle synthesis and nanofabrication technologies, [25][26][27][28] as well as the development in theories make it possible to rationally design and prepare plasmonic devices with optimal optical properties and thus enhanced sensing performance. Currently, nanostructured plasmonic sensors can be classifi ed into two main groups: colloidal nanoparticles and surface-bound nanostructures. The surface-bound nanostructures offer at least two attractive features. One is that their optical properties can be readily tuned by controlling the shape, size, composition, and spacing of the nanostructures. The other one is that they are free of capping agents or stabilizers used in colloidal nanoparticle synthesis, which makes them readily accessible for functionalization with specifi c receptors or ligands. These advantages make them the focus of research in the fi eld of plasmonic sensors.When evaluating an SP-based sensor, the refractive index sensitivity (RIS) is mostly considered. The RIS of a wavelengthinterrogated sensor is defi ned in terms of the change in peak A high-performance plasmonic biosensor based on two-dimensional (2D) Ag nanowell crystals is rationally designed and fabricated by colloidal lithography. The crystals act as 2D metallic gratings that directly couple incident photons to surface plasmon polaritons (SPPs). The nanowell sizes are properly tuned to enable coupling between the SPPs and Raleigh anomalies, which proves to greatly contribute to sharp refl ectance dips. Other geometric parameters including the nanowell depth and the lattice constant are respectively adjusted to optimize the lineshape and sensitivity. These inferences and experimental results a...