Single-molecule nucleic acid interactions monitored on a label-free microcavity biosensor platform

Biosensing relies on the detection of molecules and their specific interactions. It is therefore highly desirable to develop transducers exhibiting ultimate detection limits. Microcavities are an exemplary candidate technology for demonstrating such a capability in the optical domain and in a label-free fashion. Additional sensitivity gains, achievable by exploiting plasmon resonances, promise biosensing down to the single-molecule level. Here, we introduce a biosensing platform using optical microcavity-based sensors that exhibits single-molecule sensitivity and is selective to specific single binding events. Whispering gallery modes in glass microspheres are used to leverage plasmonic enhancements in gold nanorods for the specific detection of nucleic acid hybridization, down to single 8-mer oligonucleotides. Detection of single intercalating small molecules confirms the observation of single-molecule hybridization. Matched and mismatched strands are discriminated by their interaction kinetics. Our platform allows us to monitor specific molecular interactions transiently, hence mitigating the need for high binding affinity and avoiding permanent binding of target molecules to the receptors. Sensor lifetime is therefore increased, allowing interaction kinetics to be statistically analysed.