The detection of small molecules, such as pharmaceuticals, environmental pollutants, and chemical contaminants, is an important subject in clinical diagnostics, environmental monitoring, and food analysis. For decades, the immunoassay, as a sensitive, straightforward, and cost-effective system, has been a mainstay for the quantifiable measurement of target analytes. It is reported that the global immunoassay market was 20.93 billion dollars in 2020 and expected to reach 22.32 billion dollars in 2021 with an annual growth rate of 7.03% 5 . Immunoassays generally fall into two broad formats, competitive and noncompetitive assays, where noncompetitive assays are generally referred to as sandwich immunoassays. They essentially differ in the amount of reagent used in the immunological reaction. In a competitive immunoassay, the analyte competes with the labeled (or immobilized) analyte for the limited specific antibody. In contrast, a sandwich immunoassay can bind an analyte based on two distinct antibodies present in excess, granting a higher level of sensitivity, precision, and specificity. However, sandwich immunoassays require large analyte molecules to allow at least two epitopes to be bounded by two antibodies. Small molecules are generally not assayed by sandwich immunoassay, as they cannot be simultaneously bound by two antibodies due to steric hindrance. Since the binding pocket of the antibody against the small molecule is mostly cavitylike, the small molecule is largely buried after binding to an antibody, resulting in an inaccessible binding site for the second antibody and the failure of the sandwich immunoassay. This assumption has been reinforced by the X-ray structural analysis of hapten-antibody complexes that show how small molecules become buried deeply in the cavity-like binding site, with contacting surface areas of 200-400 Å 2 . Typical small molecules, such as drugs of abuse, antibiotics, and pesticides, possess a surface area of only 100-800 Å 2 , which theoretically is not large enough to simultaneously bind two antibodies. Therefore, sandwich immunoassays are widely used to detect macromolecules such as proteins and polypeptides, while competitive immunoassays are overwhelmingly popular for the detection of small molecules. Considering the advantages provided by sandwich immunoassays, researchers have developed alternatives for small molecule detection such as noncompetitive immunoassays based on anti-metatype or anti-idiotype antibodies, solid-phase covalent epitope immobilization, and open sandwich immunoassays. However, these strategies are greatly hindered by unconventional antibody preparation procedures and complex operation procedures, limiting the practical application of such assays. Direct sandwich immunoassays for small molecules by two distinct antibodies are rarely reported. To the best of our knowledge, true sandwich immunoassays have been reported only for a few small molecules, i.e., ciguatoxin (1023 Da), tacrolimus (804 Da), naringin (580 Da), ponatinib (533 Da), oxytetracycline (496 Da), and imatinib (494 Da); details are provided in Supplementary Table . Given one small molecule, an approach to estimate the possibility of establishing a sandwich immunoassay is currently not known. Determining the epitope distance of the analyte required to allow the binding of two antibodies can provide useful clues for the sandwich immunoassay of small molecules. Furthermore, the molecular recognition mechanism of antibodyanalyte-antibody ternary complexes in sandwich immunoassays for small molecules