Biosensors that generate a signal that is larger when the concentration of the target molecule is lower are reported online in Nature Materials this week. This inverse sensitivity allows the detection of the cancer biomarker prostate-specific antigen in whole serum at a concentration at least ten times lower than the limit of detection of current ultrasensitive assays.

Because conventional sensors generate a signal that is directly proportional to concentration, it is difficult to detect ultralow concentrations of a target molecule with confidence. Molly Stevens and colleagues designed a signal-generation mechanism that makes the signal-concentration dependence inversely proportional. They used gold nanostars as plasmonic nanosensors, and the enzyme glucose oxidase (GOx), which controls the rate of crystallization of silver nanocrystals. At low concentrations of GOx, the slow crystallization rate leads to the growth of a conformal silver coating on the nanostars, which induces a large signal in the form of a shift in their localized surface plasmon resonance. High GOx concentrations result in a smaller signal because fast crystal growth leads to the formation of silver nanocrystals in solution, and thus to less silver deposited on the nanostars.

Because GOx can be bound to antibodies, the nanosensors can be generally used to detect ultralow concentrations of antigens in enzyme-linked immunoassays. The authors also show that the nanosensors are robust against interference by other proteins.